Azabenzimidazoles as respiratory syncytial virus antiviral agents

ABSTRACT

A compound satisfying formula I, a prodrug, N-oxide, addition salt, quaternary amine, metal complex, or a stereochemically isomeric form thereof; 
                         
compositions contain these compounds as active ingredient and processes for preparing these compounds and compositions

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.13//993,141, filed Jun. 11, 2013, which is the national stage under 35U.S.C. 371 of PCT Application No. PCT/EP2011/073014, filed Dec. 16,2011, which application claims priority from European Patent ApplicationNo. EP 10195469.1, filed Dec. 16, 2010, and European Patent ApplicationNo. EP 11160724.8, filed 31 Mar. 2011 the entire disclosures of whichare hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention concerns azabenzimidazoles having antiviral activity, inparticular, having an inhibitory activity on the replication of therespiratory syncytial virus (RSV). The invention further concerns thepreparation of these azabenzimidazoles, compositions comprising thesecompounds, and the compounds for use in the treatment of respiratorysyncytial virus infection.

BACKGROUND

Human RSV or Respiratory Syncytial Virus is a large RNA virus, member ofthe family of Paramyxoviridae, subfamily pneumoviridae together withbovine RSV virus. Human RSV is responsible for a spectrum of respiratorytract diseases in people of all ages throughout the world. It is themajor cause of lower respiratory tract illness during infancy andchildhood. Over half of all infants encounter RSV in their first year oflife, and almost all within their first two years. The infection inyoung children can cause lung damage that persists for years and maycontribute to chronic lung disease in later life (chronic wheezing,asthma). Older children and adults often suffer from a (bad) common coldupon RSV infection. In old age, susceptibility again increases, and RSVhas been implicated in a number of outbreaks of pneumonia in the agedresulting in significant mortality.

Infection with a virus from a given subgroup does not protect against asubsequent infection with an RSV isolate from the same subgroup in thefollowing winter season. Re-infection with RSV is thus common, despitethe existence of only two subtypes, A and B.

Today only three drugs have been approved for use against RSV infection.A first one is ribavirin, a nucleoside analogue, that provides anaerosol treatment for serious RSV infection in hospitalized children.The aerosol route of administration, the toxicity (risk ofteratogenicity), the cost and the highly variable efficacy limit itsuse. The other two drugs, RespiGam® (RSV-IG) and Synagis® (palivizumab),polyclonal and monoclonal antibody immunostimulants, are intended to beused in a preventive way. Both are very expensive, and requireparenteral administration.

Other attempts to develop a safe and effective RSV vaccine have all metwith failure thus far. Inactivated vaccines failed to protect againstdisease, and in fact in some cases enhanced disease during subsequentinfection. Life attenuated vaccines have been tried with limitedsuccess. Clearly there is a need for an efficacious non-toxic and easyto administer drug against RSV replication. It would be particularlypreferred to provide drugs against RSV replication that could beadministered perorally.

A reference entitles “imidazopyridine and imidazopyrimidine antiviralagents” is WO 01/95910 which, in fact, relates to benzimidazoleantiviral agents. Herein compounds are presented to have antiviralactivity, yet with EC₅₀ values over a wide range of from 0.001 μM to ashigh as 50 μM (which does not normally represent the desired biologicalactivity). Another reference, relating to substituted2-methyl-benzimidazole RSV antiviral agents, in the same range ofactivities is WO 03/053344. Another related background reference oncompounds in the same range of activities, is WO 02/26228 regardingbenzimidazolone antiviral agents. A reference on structure-activityrelations, in respect of RSV inhibition, of 5-substituted benzimidazolecompounds is X. A. Wang et al., Bioorganic and Medicinal ChemistryLetters 17 (2007) 4592-4598.

It is desired to provide new drugs that have antiviral activity.Particularly, it would be desired to provide new drugs that have RSVreplication inhibitory activity. Further, it would be desired toretrieve compound structures that allow obtaining antiviral biologicalactivities of the order of magnitude in the stronger regions of theprior art (i.e. at the bottom of the above-mentioned range of up to 50μM), and preferably at a level of about the most active, more preferablyof even stronger activity, than the compounds disclosed in the art. Afurther desire is to find compounds having oral antiviral activity.

SUMMARY OF THE INVENTION

In order to better address one or more of the foregoing desires, theinvention, in one aspect, presents antiviral azabenzimidazole compoundsrepresented by formula I, a prodrug, N-oxide, addition salt, quaternaryamine, metal complex, or a stereochemically isomeric form thereof;

wherein each X independently is C or N; at least one X═N;

-   each Y independently is C or N;-   R₁ is present when X═C and R₁ is selected from the group of H,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkoxy, N(R₅)₂, CO(R₆),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    and B(OH)₂; B(O—C₁-C₆alkyl)₂;-   R₁ is absent when X═N-   R₂ —(CR₇R₈)_(n)—R₉;-   R₃ is selected from the group consisting of H, C₁-C₁₀alkyl,    C₃-C₇cycloalkyl, C₂-C₁₀alkenyl, SO₂—R₇, CH₂CF₃ or a 4 to 6 membered    saturated ring containing an oxygen atom;-   R₄ is present where Y is C and is selected from the group consisting    of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆alkoxy, CO(R₇), COO(R₇), CF₃    and halogen,-   R₅ is selected from the group consisting of H, C₁-C₆alkyl, COOCH₃,    and CONHSO₂CH₃;-   R₆ is selected from the group consisting of OH, O(C₁-C₆alkyl), NH₂,    NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), and N(C₁-C₆-alkyl)₂;-   R₇ and R₈ are each independently chosen from H, C₁-C₁₀alkyl,    C₃-C₇cycloalkyl or R₇ and R₈ taken together form a 4 to 6 membered    aliphatic ring that optionally contains a heteroatom selected from    the group N, S, O;

R₉ is selected from the group consisting of H, R₁₀, C₁-C₆alkyl, OH, CN,F, CF₂H, CF₃, CONR₇R₈, COOR₇, CON(R₇)SO₂R₈, CON(R₇)SO₂N(R₇R₈), NR₇R₈,NR₇COOR₈, OCOR₇, O-Benzyl, NR₇SO₂R₈, SO₂NR₇R₈, SO₂R₇, OCONR₇R₈,OCONR₇R₁₀, N(R₇)CON(R₇R₈), N(R₇)COOR₁₀; phtalimido,2-methyl-benzothiophene(1,1)dioxide, or a 4 to 6 membered saturated ringcontaining an oxygen atom;

-   n is an integer from 2 to 6;-   R₁₀ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridine or pyrazole, optionally    substituted with one or more substituents selected from the group    comprising CF₃, CH₃, OCH₃, OCF₃ or halogen.

In an embodiment according to the invention,

R₃ is selected from the group consisting of H, C₁-C₁₀alkyl,C₃-C₇cycloalkyl, C₂-C₁₀alkenyl, SO₂—R₇, or a 4 to 6 membered saturatedring containing an oxygen atom; and R₉ is selected from the groupconsisting of H, C₁-C₆alkyl, OH, CN, F, CF₂H, CF₃, CONR₇R₈, COOR₇,CON(R₇)SO₂R₈, CON(R₇)SO₂N(R₇R₈), NR₇R₈, NR₇COOR₈, OCOR₇, O-Benzyl,NR₇SO₂R₈, SO₂NR₇R₈, SO₂R₇ or a 4 to 6 membered saturated ring containingan oxygen atom;

-   n is an integer from 2 to 6.

In another aspect, the invention relates to the foregoing compounds foruse in the treatment of RSV infections in warm-blooded animals,preferably humans. In yet another aspect, the invention presents amethod of treatment of viral RSV infections in a subject in needthereof, comprising administering to said subject an effective amount ofa compound as defined above. In still another aspect, the inventionresides in the use of a compound as defined above, for the manufactureof a medicament in the treatment of RSV infections.

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising a compound as defined above, and apharmaceutically acceptable excipient.

In a still further aspect, the invention provides methods for preparingthe compounds defined above.

DETAILED DESCRIPTION OF THE INVENTION

The molecules of formula I, in deviation from the prior art, have on oneside (the left side in the formula as depicted) a substitutedazabenzimidazole moiety. The invention, in a broad sense, is based onthe judicious recognition that these substituted azabenzimidazolecompounds generally possess an interesting RSV inhibitory activity.Moreover, these compounds enable access to anti-RSV activities at thehigher regions (i.e. the lower end of the EC₅₀ values) of the rangeavailable in the aforementioned references. Particularly, on the basisof these compounds, molecular structures can be uncovered that evenoutperform the reference compounds in terms of biological activities.

The present invention will further be described with respect toparticular embodiments and with reference to certain examples but theinvention is not limited thereto but only by the claims. Where the term“comprising” is used in the present description and claims, it does notexclude other elements or steps. Where an indefinite or definite articleis used when referring to a singular noun e.g. “a” or “an”, “the”, thisincludes a plural of that noun unless something else is specificallystated.

The term ‘prodrug’ as used throughout this text means thepharmacologically acceptable derivatives, e.g. esters and amides, suchthat the resulting biotransformation product of the derivative is theactive drug as defined in the compounds of formula (I). The reference byGoodman and Gilman (The Pharmacological Basis of Therapeutics, 8^(th)ed., a McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p.13-15) describing prodrugs generally, is hereby incorporated. Prodrugsare characterized by a good aqueous solubility and bioavailability, andare readily metabolized into the active inhibitors in vivo.

As used herein C₁-C₆alkyl as a group or part of a group defines straightor branched chain saturated hydrocarbon radicals having from 1 to 6carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl,pentyl, hexyl, 2-methylbutyl and the like.

C₁-C₁₀alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 10 carbon atomssuch as the groups defined for C₁₋₆alkyl and heptyl, octyl, nonyl,2-methylhexyl, 2-methylheptyl, decyl, 2-methylnonyl, and the like.Optionally, C₁₋₁₀alkyl includes a cycloalkyl moiety, preferably acyclopropyl moiety, e.g. methylcyclopropyl, ethylcyclopropyl, and thelike.

The term ‘C₂-C₁₀alkenyl’ used herein as a group or part of a group ismeant to comprise straight or branched chain unsaturated hydrocarbonradicals having at least one double bond, and preferably having onedouble bond, and from 2 to 10 carbon atoms such as ethenyl, propenyl,buten-1-yl, buten-2-yl, penten-1-yl, penten-2-yl, hexen-1-yl,hexen-2-yl, hexen-3-yl, 2-methylbuten-1-yl, hepten-1-yl, hepten-2-yl,hepten-3-yl, hepten-4-yl, 2-methylhexen-1-yl, octen-1-yl, octen-2-yl,octen-3-yl, octen-4-yl, 2-methylhepten-1-yl, nonen-1-yl, nonen-2-yl,nonen-3-yl, nonen-4-yl, nonen-5-yl, 2-methylocten-1-yl, decen-1-yl,decen-2-yl, decen-3-yl, decen-4-yl, decen-5-yl, 2-methylnonen-1-yl, andthe like;

Whenever a C₂-C₁₀alkenyl group is linked to a heteroatom it preferablyis linked via a saturated carbon atom.

C₁-C₆alkoxy, as a group or part of a group defines an O—C₁-C₆alkylradical, wherein C₁-C₆alkyl has, independently, the meaning given above.

C₃-C₇cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

The term —(CR₇R₈)_(n) used herein defines n repetitions of the CR₇R₈subgroup, wherein each of these subgroups is independently defined.

The term halogen is generic to fluoro, chloro, bromo and iodo.

It should be noted that the radical positions on any molecular moietyused in the definitions may be anywhere on such moiety as long as it ischemically stable.

Radicals used in the definitions of the variables include all possibleisomers unless otherwise indicated. For instance pentyl includes1-pentyl, 2-pentyl and 3-pentyl.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

Whenever used hereinafter, the term “compounds of formula (I)”, or “thepresent compounds” or similar term is meant to include the compounds ofgeneral formula (I), their prodrugs, N-oxides, addition salts,quaternary amines, metal complexes and stereochemically isomeric forms.

It will be appreciated that some of the compounds of formula (I) maycontain one or more centers of chirality and exist as stereochemicallyisomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible compounds made up of the same atoms bonded by the samesequence of bonds but having different three-dimensional structureswhich are not interchangeable, which the compounds of formula (I) maypossess.

Unless otherwise mentioned or indicated, the chemical designation of acompound encompasses the mixture of all possible stereochemicallyisomeric forms which said compound may possess. Said mixture may containall diastereomers and/or enantiomers of the basic molecular structure ofsaid compound. All stereochemically isomeric forms of the compounds ofthe present invention both in pure form or in admixture with each otherare intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates asmentioned herein are defined as isomers substantially free of otherenantiomeric or diastereomeric forms of the same basic molecularstructure of said compounds or intermediates. In particular, the term‘stereoisomerically pure’ concerns compounds or intermediates having astereoisomeric excess of at least 80% (i e minimum 90% of one isomer andmaximum 10% of the other possible isomers) up to a stereoisomeric excessof 100% (i.e. 100% of one isomer and none of the other), more inparticular, compounds or intermediates having a stereoisomeric excess of90% up to 100%, even more in particular having a stereoisomeric excessof 94% up to 100% and most in particular having a stereoisomeric excessof 97% up to 100%. The terms ‘enantiomerically pure’ and‘diastereomerically pure’ should be understood in a similar way, butthen having regard to the enantiomeric excess, respectively thediastereomeric excess of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of thisinvention may be obtained by the application of art-known procedures.For instance, enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids or bases. Examples thereof are tartaric acid,dibenzoyl-tartaric acid, ditoluoyltartaric acid and camphosulfonic acid.Alternatively, enantiomers may be separated by chromatographictechniques using chiral stationary phases. Said pure stereochemicallyisomeric forms may also be derived from the corresponding purestereochemically isomeric forms of the appropriate starting materials,provided that the reaction occurs stereospecifically. Preferably, if aspecific stereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

The diastereomeric racemates of formula (I) can be obtained separatelyby conventional methods. Appropriate physical separation methods thatmay advantageously be employed are, for example, selectivecrystallization and chromatography, e.g. column chromatography.

For some of the compounds of formula (I), their prodrugs, N-oxides,salts, solvates, quaternary amines, or metal complexes and theintermediates used in the preparation thereof, the absolutestereochemical configuration was not experimentally determined A personskilled in the art is able to determine the absolute configuration ofsuch compounds using art-known methods such as, for example, X-raydiffraction.

The present invention is also intended to include all isotopes of atomsoccurring on the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds offormula (I) are able to form. The pharmaceutically acceptable acidaddition salts can conveniently be obtained by treating the base formwith such appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioicacid), tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term addition salt as used hereinabove also comprises the solvates,which the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) are able to form byreaction between a basic nitrogen of a compound of formula (I) and anappropriate quaternizing agent, such as, for example, an optionallysubstituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude chloro, bromo, iodo, trifluoroacetate and acetate. Thecounterion of choice can be introduced using ion exchange resins.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

It will be appreciated that the compounds of formula (I) may have metalbinding, chelating, complexating properties and therefore may exist asmetal complexes or metal chelates. Such metalated derivatives of thecompounds of formula (I) are intended to be included within the scope ofthe present invention.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

It will be appreciated that the compounds of the invention, withreference to the aforementioned left- and right-hand parts of formula I,present a wide variety of modification.

Without detracting from the overall scope of the invention, certainembodiments are discussed in more detail below.

In a preferred embodiment at most two X are N. In a preferredembodiment, one X is N. In a more preferred embodiment, the one X thatis N is located in meta position to the N—R₂ group of the imidazolering, and said N is located in ortho position to the ═N-atom of theimidazole ring.

In one preferred embodiment, R₁ is selected from the group consisting ofH, halogen, and CH₂—NH₂. In a further preferred embodiment, R₁ in thepara position to C—N—R₂ is selected from the group consisting of H,halogen, and CH₂—NH₂, and all other R₁ are H. In a further preferredembodiment halogen is bromo or chloro. In a most preferred embodiment,at most one R₁ is chloro, and all other R₁ are H. In yet an even morepreferred embodiment, R₁ in the para position to C—N—R₂ is chloro.

In another preferred embodiment, R₂ comprises a —(CR₇R₈)_(n)—R₉ chainwherein R₂ and R₈ are preferably H and n is 2-4. Preferably R₉ isselected from the group consisting of OH, C₁-C₆alkyl, more preferably2-propyl, C₁-C₆alkoxy, more preferably methoxy, SO₂R₇, with R₂preferably being methyl. Most preferably R₉ is fluoro or CF₃.

In a preferred embodiment R₃ is selected from the group consisting ofC₃-C₇cycloalkyl, more preferably cyclopropyl, and a 4 membered saturatedhydrocarbon containing an oxygen atom.

In a preferred embodiment, and more preferably in conjunction with theother preferred embodiments, one Y is N, and the other Y's are C. In amost preferred embodiment, the one Y that is N, is the Y in paraposition to N—R₃.

Preferably at most one R₄ is halogen, preferably fluoro. Mostpreferably, all R₄ are H.

Preferred compounds are the compounds listed below. More preferred arecompounds number 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 16, 17, 18, 19, 20,21, 31, 32, 33, 34, 35, and 36. Most preferred are compounds number 1,2, 16, 31, 32, and 33.

The compounds of formula I may be prepared by the methods describedbelow, using synthetic methods known in the art of organic chemistry, ormodifications and derivatisations that are familiar to those skilled inthe art. The starting materials used herein are commercially availableor may be prepared by routine methods known in the art such as thosemethods disclosed in standard reference books. Preferred methodsinclude, but are not limited to, those described below.

During any of the following synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999,which are hereby incorporated by reference.

Compounds of formula I, or their pharmaceutically acceptable salts, canbe prepared according to the reaction schemes discussed herein below.Unless otherwise indicated, the substituent in the schemes are definedas above. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

Scheme 1 illustrates a method for the preparation of compounds offormula I, where R₁ to R₄, X and Y are defined as above.

Referring to scheme 1, a compound of formula I can be synthesized bycoupling 2-hydroxymethylene imidazopyridines II-a with N³-substituted2-oxo-imidazopyridine or with N³-substituted 2-oxo-imidazobenzene III ina known in the art method such as a Mitsunobu reaction which usesazadiisopropyldicarboxylate and triphenyl phosphine in a suitablesolvent such as DMF or THF. Alternatively, compound of formula I may beprepared by displacement of Z, which is a halide, preferably chlorineII-b, or a sulfonate such as mesylate II-c in the presence of a basesuch as sodium hydride, potassium carbonate or cesium carbonate in asuitable solvent such as DMF or THF.

Preparation of Compound II-b and II-c

Treatment of the alcohol II-a with thionyl chloride provides2-chloromethyl imidazopyridines II-b. Alternatively, alcohol II-a may betransformed to the intermediate II-c by a reaction with methane sulfonylchloride in the presence of an organic base such as triethyl amine ordiisopropyl ethyl amine in a suitable solvent such as dichloromethane(scheme 2).

Preparation of Compound II-a

Compounds of formula II-a are either commercially available or can beprepared, but not limited to, by general procedures illustrated byscheme 3, wherein R₁, R₂, X are defined as above. Referring to scheme 3below, haloheteroaryls IV, where W is an halide preferably fluorine, canbe treated with primary amines of formula V in the presence of asuitable base such as potassium carbonate and the like, in a suitablesolvent such as ethanol or dichloromethane at a reaction temperatureranging from room temperature to 100° C. to give compounds of formulaVI. Hydrogenation of the nitro group using well-precedented conditionssuch as Pd/C, or other catalyst, under hydrogen or Fe/EtOH/CaCl₂ canyield diamine of formula VII. Alternatively, the hydrogenation of thenitro group of compound VIII using well-precedented conditions such asPd/C, or other catalyst, under hydrogen or Fe/EtOH/CaCl₂ yield diamineof formula IX which can be treated with the aldehydes of formula X inthe presence of suitable reducing agents such as NaBH(OAc)₃, orNa(CN)BH₃ in solvents such as methylene chloride, DMF or THF, at aboutroom temperature gives compounds of formula VII. The imidazol ring canbe formed by treating diamines VII with glycolic acid or an ester likeXIII under strong acidic conditions, such as aqueous hydrochloric acid,at elevated temperature such as reflux to yield the alcohols of formulaII-a. Alternatively, diamines VII can be condensed with dialkoxyacetateof formula XII, in the presence of acetic acid, in a suitable solventsuch as methanol gives the acetal II-e. The acetal of compounds II-e canbe removed with acids such as hydrochloric acid to give the aldehydes offormula II-f. The resulting aldehydes of formula II-f can be reduced toalcohols using a suitable reducing agent such as NaBH₄ or LiAlH₄ in asuitable solvent such as ethanol or THF to yield the desired alcohols offormula II-a. In addition, diamines VII can be cyclized with dialkyloxalate of formula XI in a suitable solvent such as ethanol at elevatedtemperature with or without microwave heating to produce imidazoles offormula II-d. Alternatively, compounds of formula II-d may be preparedin a two steps synthesis starting from diamines VII. Firstly diamine VIImay be reacted with an alkyl trihaloacetimidate, preferably methyl2,2,2-trichloroacetimidate, in an acidic media, preferably acetic acid,at a temperature ranging between 25 and 50° C. to yield compound offormula II-g. Secondly a reaction of compounds of formula II-g withmetalcarbonate, preferably sodium carbonate in a suitable solvent suchas methanol, lead to compounds of formula II-d. Compounds II-d can besubsequently reduced to the desired alcohols of formula II-a using asuitable reducing agent such as NaBH₄ or LiAlH₄ in a suitable solventsuch as ethanol or THF.

An alternative route for the preparation of compounds of type II-a isdepicted in scheme 4. Diamine IX may be first coupled to an alkylglycolic acid or an ester like XIII under strong acidic conditions, suchas aqueous hydrochloric acid, at elevated temperature such as reflux toyield the alcohols of formula XIV. This alcohol may be protected by aPG, where PG is a protecting group such as, but not limiting to, atrityl which consequently results in compounds XV. A suitable solventfor this type of reactions can be, but not limiting to, dichloromethane.The treatment of compound XV with compound XVI, wherein the LG is aleaving group, such as halide, preferably bromine, or sulfonate, in thepresence of a base such as sodium hydride, potassium carbonate or cesiumcarbonate in a suitable solvent such as DMF or THF, gives compound II-h.The removal of the PG in compound II-h may be done in the presence of anacid such as hydrochloric acid in the presence of a solvent, not limitedto, such as dioxane to yield compound II-a.

Compounds III can be synthesized using the procedure depicted in scheme5. Displacement of W, which is a halide, preferably fluorine, or analkoxy group, preferably methoxy, of nitro pyridine or of nitro arylXVII with an amine, in a suitable solvent such as THF or DMF, in thepresence of an organic base such as triethylamine or diisopropyl ethylamine, gives compound XVIII. Reduction of the nitro group to the amineXIX can be done in a catalytic way using hydrogen in the presence of acatalyst such as palladium or platinum, in a suitable solvent such asmethanol, or in a stoichiometric way using iron in the presence ofammonium chloride or tin chloride in the presence of concentratedhydrochloric acid. The cyclisation of the resulting diamine XIX usingCDI, phosgene or triphosgene, in a solvent such as acetonitril or THF,provides N³-substituted 2-oxo-imidazopyridine or N³-substituted2-oxo-imidazobenzen III. Alternatively, compound of type III may beprepared starting from commercially available dianilines XX which can becyclized by ring closure with CDI, phosgene or triphosgene and yieldsintermediates of type XXI. Alkylation of the urea nitrogen of XXI can beaccomplished by a Mitsunobu reaction with commercially availablealcohols, and sulfonylation by displacement of the chlorine in thecompounds of type XXII to yield compounds of formula III.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.t.butyl hydro-peroxide. Suitable solvents are, for example, water, loweralcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g., counter-current distribution,liquid chromatography and the like.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) which are sufficiently basic oracidic may be converted into the corresponding diastereomeric salt formsby reaction with a suitable chiral acid, respectively chiral base. Saiddiastereomeric salt forms are subsequently separated, for example, byselective or fractional crystallization and the enantiomers areliberated therefrom by alkali or acid. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography, in particular liquid chromatographyusing a chiral stationary phase. Said pure stereochemically isomericforms may also be derived from the corresponding pure stereochemicallyisomeric forms of the appropriate starting materials, provided that thereaction occurs stereospecifically. Preferably if a specificstereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

In a further aspect, the present invention concerns a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) as specified herein, or a compound of any of theembodiments of compounds of formula (I) as specified herein, and apharmaceutically acceptable carrier. A therapeutically effective amountin this context is an amount sufficient to prophylaxictically actagainst, to stabilize or to reduce viral infection, and in particularRSV viral infection, in infected subjects or subjects being at risk ofbeing infected. In still a further aspect, this invention relates to aprocess of preparing a pharmaceutical composition as specified herein,which comprises intimately mixing a pharmaceutically acceptable carrierwith a therapeutically effective amount of a compound of formula (I), asspecified herein, or of a compound of any of the embodiments ofcompounds of formula (I) as specified herein.

Therefore, the compounds of the present invention or any embodimentthereof may be formulated into various pharmaceutical forms foradministration purposes. As appropriate compositions there may be citedall compositions usually employed for systemically administering drugs.To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, optionally in addition saltform or metal complex, as the active ingredient is combined in intimateadmixture with a pharmaceutically acceptable carrier, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, particularly, foradministration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed such as, forexample, water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin.

The compounds of the present invention may also be administered via oralinhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder, a solution beingpreferred. Any system developed for the delivery of solutions,suspensions or dry powders via oral inhalation or insufflation aresuitable for the administration of the present compounds.

Thus, the present invention also provides a pharmaceutical compositionadapted for administration by inhalation or insufflation through themouth comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier. Preferably, the compounds of the present inventionare administered via inhalation of a solution in nebulized oraerosolized doses.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills,suppositories, powder packets, wafers, injectable solutions orsuspensions and the like, and segregated multiples thereof.

The compounds of formula (I) show antiviral properties. Viral infectionstreatable using the compounds and methods of the present inventioninclude those infections brought on by ortho- and paramyxoviruses and inparticular by human and bovine respiratory syncytial virus (RSV). Anumber of the compounds of this invention moreover are active againstmutated strains of RSV. Additionally, many of the compounds of thisinvention show a favorable pharmacokinetic profile and have attractiveproperties in terms of bioavailabilty, including an acceptablehalf-life, AUC and peak values and lacking unfavourable phenomena suchas insufficient quick onset and tissue retention.

The in vitro antiviral activity against RSV of the present compounds wastested in a test as described in the experimental part of thedescription, and may also be demonstrated in a virus yield reductionassay. The in vivo antiviral activity against RSV of the presentcompounds may be demonstrated in a test model using cotton rats asdescribed in Wyde et al. (Antiviral Research (1998), 38, 31-42).

Due to their antiviral properties, particularly their anti-RSVproperties, the compounds of formula (I) or any embodiment thereof,their prodrugs, N-oxides, addition salts, quaternary amines, metalcomplexes and stereochemically isomeric forms, are useful in thetreatment of individuals experiencing a viral infection, particularly aRSV infection, and for the prophylaxis of these infections. In general,the compounds of the present invention may be useful in the treatment ofwarm-blooded animals infected with viruses, in particular therespiratory syncytial virus.

The compounds of the present invention or any embodiment thereof maytherefore be used as medicines. Said use as a medicine or method oftreatment comprises the systemic administration to viral infectedsubjects or to subjects susceptible to viral infections of an amounteffective to combat the conditions associated with the viral infection,in particular the RSV infection.

The present invention also relates to the use of the present compoundsor any embodiment thereof in the manufacture of a medicament for thetreatment or the prevention of viral infections, particularly RSVinfection.

The present invention furthermore relates to a method of treating awarm-blooded animal infected by a virus, or being at risk of infectionby a virus, in particular by RSV, said method comprising theadministration of an anti-virally effective amount of a compound offormula (I), as specified herein, or of a compound of any of theembodiments of compounds of formula (I), as specified herein.

In general it is contemplated that an antivirally effective daily amountwould be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administerthe required dose as two, three, four or more sub-doses at appropriateintervals throughout the day. Said sub-doses may be formulated as unitdosage forms, for example, containing 1 to 1000 mg, and in particular 5to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines.

Also, the combination of another antiviral agent and a compound offormula (I) can be used as a medicine. Thus, the present invention alsorelates to a product containing (a) a compound of formula (I), and (b)another antiviral compound, as a combined preparation for simultaneous,separate or sequential use in antiviral treatment. The different drugsmay be combined in a single preparation together with pharmaceuticallyacceptable carriers. For instance, the compounds of the presentinvention may be combined with interferon-beta or tumor necrosisfactor-alpha in order to treat or prevent RSV infections.

The invention will hereinafter be illustrated with reference to thefollowing, non-limiting examples.

EXAMPLE 1

Synthesis of Intermediates

All the intermediates needed for the synthesis of targeted compounds offormula I are synthesized as described in the following schemes 6 to 14.

Step 1: Synthesis of 3-(methylsulfonyl)propan-1-ol 6-b

The 3-(methylthio)propan-1-ol 6-a (200 g, 1900 mmol, CAS 505-10-2) wasdissolved in CH₂Cl₂ (2000 mL). The mixture was cooled to 0° C. Them-CPBA 85% in water (970 g, 5700 mmol, CAS 937-14-4) was added portionwise keeping the temperature between 0 and 5° C. After addition, themixture was allowed to warm to 25° C. and stirred for 15 h. The mixturewas filtered through a celite pad. The filtrate was purified by flashcolumn (Eluent: petroleum ether:ethyl acetate=3:1 and then ethylacetate:methanol=10:1) to yield the intermediate 6-b (75 g, 29%).

Step 2: Synthesis of 1-bromo-3-(methylsulfonyl)propane 6-c

The intermediate 6-b (75 g, 543 mmol) was dissolved in CH₂Cl₂ (750 mL).The mixture was cooled to 0° C. The phosphorus tribromide (53.6 mL, 570mmol) was added dropwise keeping the temperature between 0 and 5° C.After addition, the mixture was allowed to warm to 25° C. and stirredfor 15 h. The mixture was poured into ice-water. The separated organiclayer was washed with brine (2×500 mL), dried over Na₂SO₄, filtered andevaporated under vacuum to yield the title compound 6-c (77 g, 71%). ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 2.25-2.40 (m, 2 H) 2.91 (s, 3 H)3.1-3.2 (m, 2H) 3.5-3.6 (m, 2H).

Step 3: Synthesis ofN-(diphenylmethylene)-3-(methylsulfonyl)propan-amines 6-d

The intermediate 6-c (27 g, 134 mmol) was dissolved in CH₃CN (60 mL).Diphenylmethanimine (27 g, 148 mmol) and DIEA (19.6 g, 152 mmol) wasadded. The mixture was refluxed for 4 h and then cooled to roomtemperature. The mixture was neutralized with 50% aqueous acetic acid at25° C. Water (80 mL) was added. The mixture was extracted with ethylacetate (2×300 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and evaporated under vacuum. The residue waswashed with petroleum ether (4×100 mL). The mixture was treated withmethyl tert-butyl ether. The solid was collected and washed withpetroleum ether. The filtrate was dried under vacuum. The residue waspurified by column chromatography (Eluent: CH₂Cl₂:ethyl acetate from 1:0to 10:1). The title compound 6-d was obtained as a white solid (34 g,85%).

Step 4: Synthesis of 3-(methylsulfonyl)propan-1-amine hydrochloride 6-e

The intermediate 6-d (34 g, 113 mmol) was dissolved in dioxane (600 mL).The mixture was cooled to 0-5° C. and a solution of 4N HCl/dioxane (120mL, 480 mmol) was added dropwise. After addition, the mixture wasallowed to warm to 25° C. and stirred for 15 h. The mixture wasfiltered. The solid was collected and washed with dioxane. The titleproduct 6-e was obtained as a yellow powder (11.5 g, 50%).

4-Chlorobutan-1-ol 7-a (100 g, 920 mmol, CAS 928-51-8) was dissolved inCH₂Cl₂ (1000 mL) at room temperature. The mixture was cooled to 0° C.then Imidazole (81.5, 1200 mmol) and TBDMS-Cl (152 g, 1010 mmol) wereadded. The resulting mixture was stirred for 4 hours at room temperaturethen filtered off. The filtrate was washed successively with an aqueoussolution 10% of HCl and with brine. The resulting solution was driedover MgSO₄, filtered then concentrated to yield the title compounds 7-bas a colorless oil (100 g, 50%).

A mixture of 4-aminobutan-1-ol 8-a (50 g, 561 mmol, CAS 13325-10-5),imidazole (167 g, 2450 mmol), and tert-butylchlorodiphenylsilane (170 g,618 mmol, CAS 58479-61-1) in CH₂Cl₂ (1500 mL) was stirred at 25° C. for15 hours. The resulting mixture was washed successively with saturatedNaHCO₃ (2×800 mL), water (2×800 mL) and brine (2×500 mL). The organiclayer was separated, dried over Na₂SO₄, filtered and evaporated undervacuum. The product 8-b was obtained as an oil (200 g, 95%).

Step 1: Synthesis of 4-(methylthio)butan-1-ol 9-a

4-Chlorobutan-1-ol 7-a (180 g, 1658 mmol, CAS 928-51-8) was added tosodium thiomethoxide (656 g, 1965 mmol, 21% solution in water) at 0-5°C. After addition, the mixture was allowed to warm to 25° C. and stirredfor 48 h. The mixture was extracted with CHCl₃. The separated organiclayer was dried over Na₂CO₃, filtered and evaporated under vacuum. Theresidue was distilled to afford the alcohol 9-a as an oil (144.2 g,72%).

Step 2: Synthesis of 4-(methylsulfonyl)butan-1-ol 9-b

The intermediate 9-a (141 g, 1173 mmol) was dissolved in CH₂Cl₂ (9000mL). The mixture was cooled to 0-5° C. m-CPBA (483 g, 85% purity, 2375mmol, CAS 937-14-4) was added portion wise at 0-5° C. After addition,the mixture was allowed to warm to 25° C. and stirred for 15 hours. Themixture was filtered through a celite pad. The filtrate was purified byflash column (Eluent: petroleum ether:ethyl acetate=3:1 and then ethylacetate:methanol=10:1). This yielded product 9-b (98 g, 65%).

Step 3: Synthesis of 1-bromo-4-(methylsulfonyl)butane 9-c

The intermediate 9-b (98 g, 645 mmol) was dissolved in CH₂Cl₂ (1100 mL).The mixture was cooled to 0-5° C. PBr₃ (64 mL, 674 mmol) was addeddropwise at 0-5° C. After addition, the mixture was allowed to warm to25° C. and stirred for 15 hours. The mixture was poured into ice-water.The separated organic layer was washed with brine (2×500 mL), dried overNa₂SO₄, filtered and evaporated under vacuum. The product 9-c wasobtained (84.5 g, 80%).

Step 1: Synthesis of N-cyclopropyl-3-nitropyridin-4-amine 10-b

The mixture of 4-methoxy-3-nitropyridine 10-a (200 g, 1300 mmol, CAS31872-62-5), cyclopropylamine (185.5 g, 3250 mmol) and diisopropyl ethylamine (336 g, 2600 mmol) in dry ethanol (800 mL) was refluxed for 3hours. The mixture was cooled to 0° C. The solid was collected byfiltration. The filter cake was washed with cold ethanol (150 mL). Thesolid was dried to afford the title compound 10-b as a white powder (167g, 72%).

Step 2: Synthesis of N⁴-cyclopropylpyridin-3,4-diamine 10-c

Intermediate 10-b (167 g, 932 mmol) in ethanol (1400 mL) washydrogenated (50 Psi) at 20° C. with wet 10% Pd/C (34 g) as a catalystovernight. After uptake of H₂ (3 eq), the catalyst was filtered off andthe filtrate was evaporated. The residue was washed with methyltert-butyl ether to afford the title compound 10-c as a yellow powder(133 g, 95%).

Step 3: Synthesis of 1-cyclopropyl-1H-imidazo[4,5-c]pyridine-2(3H)-one10-d

Carbonyldiimidazole (151.8 g, 936 mmol) was added to a solution ofintermediate 10-c (133 g, 891.4 mmol) in CH₃CN (1800 mL) at 0° C. Thereaction mixture was allowed to warm to 10° C. and stirred for 1 h. Thesolid was collected by filtration and was washed with CH₃CN (200 mL) toafford the title compound 10-d as a white powder (101 g, 65%).

Compound 11-d was prepared in the same manner as compound 10-d using3-aminooxetane as starting material.

Step 1: Synthesis of N-cyclopropyl-4-fluoro-2-nitroaniline 12-b

The 1,4-difluoro-2-nitrobenzene 12-a (CAS 364-74-9) (15 g, 94.3 mmol)was dissolved in DMF (500 mL). Cyclopropyl amine (7 mL, 100 mmol) wasadded followed by triethylamine (30 mL, 217 mmol). The resulting mixturewas stirred at room temperature overnight. The mixture was poured inwater and extracted with dichloromethane dried over MgSO₄ andconcentrated. The orange solid was purified by column chromatographyusing dichloromethane and methanol to yield the intermediate 12-b as anorange solid (16 g, 86%).

m/z=197 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.63-0.68 (m, 2 H),0.88-0.95 (m, 2 H), 2.54-2.55 (m, 1 H), 7.27-7.34 (m, 2 H), 7.84-7.90(m, 1 H), 7.93-8.02 (m, 1 H).

Step 2: Synthesis of N¹-cyclopropyl-4-fluorobenzene-1,2-diamine 12-c

Intermediate 12-b (16 g, 82 mmol) in ethanol (200 mL) was hydrogenatedat room temperature with wet 10% Pd/C as a catalyst overnight. Afteruptake of H₂ (3 eq), the catalyst was filtered off and the filtrate wasevaporated. The residue was washed with ethanol to afford the titlecompound 9-c as a white solid (12.8 g, 94%). m/z=167 (M+H)⁺.

Step 3: Synthesis of1-cyclopropyl-5-fluoro-1H-benzo[d]imidazol-2(3H)-one 12-d

Carbonyldiimidazole (13.15 g, 81 mmol) was added to a solution ofintermediate 12-c (12.8 g, 77.3 mmol) in CH₃CN (150 mL) at 0° C. Thereaction was allowed to warm up to room temperature and stirred for 4hours. The solvent was removed, then the residue was purified by columnchromatography using CH₂Cl₂/methanol to yield a light brown solid whichwas triturated in diethyl ether to yield compound 12-d as a white solid(7.4 g, 50%). m/z=193 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.08 (m, 2 H) 1.08-1.20 (m, 2H) 2.89 (m, 1 H) 6.75-6.84 (m, 1 H) 6.87 (dd, J=8.53, 2.51 Hz, 1 H) 7.10(dd, J=8.53, 4.27 Hz, 1 H) 10.33 (br. s., 1 H).

Compound 13-d was prepared in the same manner as compound 12-d using2-fluoronitrobenzene 13-a as starting material.

Compound 14-d was prepared in the same manner as compound 12-d using2,4-dichloro-3-nitropyridine 14-a and isopropyl amine as startingmaterials.

EXAMPLE 2 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one1

Step 1: Synthesis of 6-chloropyridine-2,3-diamine 1-1

To a mixture of ethyl acetate (450 mL) and tert-butanol (50 mL),6-chloro-3-nitropyridin-2-amine (CAS 27048-04-0) (15 g, 86,42 mmol),stannous chloride dehydrate (CAS 10025-69-1) (97.5 g, 432.1 mmol) wereadded. The resulting mixture was stirred at 60° C. for 1 hour.Sodiumborohydride (1.63 g, 43.21 mmol) was added and the mixture wasstirred further at 60° C. for another 3 h. The mixture was cooled andstripped from the EtOAc on the rotavapor. The resulting residu wasdiluted with water (350 mL) and neutralized to pH=9-10 by addition of anaqueous solution of potassium carbonate. The resulting mixture wasextracted with EtOAc (3×250 mL), dried over Na₂SO₄ and evaporated. Theresidu was stirred for 72 hours in a mixture of EtOAc/heptane 1/1. Theprecipitate was filtered and dried in vacuum for 2 hours. Theintermediate 1-1 was collected as a greenish powder (9.32 g, 75%).m/z=144 (M+H)⁺.

Step 2: Synthesis of 6-chloro-N³-isopentylpyridine-2,3-diamine 1-2

The intermediate 1-1 (5 g, 34.82 mmol) was dissolved in dichloromethane(200 mL), acetic acid (20 drops) and 4-methylpentanal (3 g, 34.8 mmol,CAS 1119-16-0) were added. The resulting mixture was stirred for 30minutes and then sodium triacetoxyhydroborate (22.14 g, 104.5 mmol) wasadded. The reaction mixture was stirred at room temperature overnightand a solution of 50% Na₂CO₃ was added dropwise until gas evolutionstopped. The organic layer was separated, dried on MgSO₄, filtrated andevaporated to dryness. The residu was purified by column chromatographyusing heptane/EtOAc 7/3 to pure EtOAc. Compound 1-2 was recovered as awhite solid and dried in vacuo overnight (4.8 g, 65%). m/z=214 (M+H)⁺.

Step 3: Synthesis of(5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methanol 1-3

A mixture of intermediate 1-2 (4.8 g, 22.46 mmol) and 2-hydroxyaceticacid (4.27 g, 56.2 mmol) was stirred at 150° C. for 4 hours. The mixturewas allowed to cool down to room temperature and treated carefully with3N hydrochloric acid. The resulting mixture was made basic with aqueousammonia and extracted with CH₂Cl₂ (300 mL). The organic layer was driedover MgSO₄ and evaporated to dryness. The residu was purified by columnchromatography on silica using CH₂Cl₂ to EtOAc. The product 1-3 wasisolated as brown solid (3.5 g, 61%).

m/z=255 (M+H)⁺.

Step 4: Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one1

To a stirred solution of intermediate 1-3 (0.29 g, 1.14 mmol), triphenylphosphine (0.33 g, 1.25 mmol) and the pyridobenzimidazolone 10-d (0.22g, 1.25 mmol) in dry THF (30 mL) was added DIAD (94%, 0.287 mL, 1.37mmol) dropwise at room temperature. The reaction mixture was stirredovernight. After completion of the reaction, the mixture wasconcentrated to dryness the residue was purified by columnchromatography eluted with ethyl acetate/CH₂Cl₂ then CH₂Cl₂/methanol toyield the title compound 1 as a white solid (233 mg, 50%). m/z=412(M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.06 (m, 2 H), 0.99 (d, J=6.5Hz, 6 H), 1.17 (m, 2 H), 1.52 (m, 1 H), 1.64-1.76 (m, 2 H), 2.85-2.96(m, 1 H), 4.30-4.41 (m, 2 H), 5.37 (s, 2 H), 7.13 (d, J=5.3 Hz, 1 H),7.23 (d, J=8.5 Hz, 1 H), 7.60 (d, J=8.5 Hz, 1 H), 8.35 (d, J=5.3 Hz, 1H), 8.69 (s, 1 H)

EXAMPLE 3 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(oxetan-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one2

Compound 2 was synthesized in the same manner as compound 1 usingintermediates 1-3 and 11-d as starting material. m/z=428 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 (d, J=6.8 Hz, 6 H), 1.51-1.61(m, 2 H), 1.70 (m, 1 H), 4.29-4.41 (m, 2 H), 5.07-5.18 (m, 4 H), 5.40(s, 2 H), 5.56-5.67 (m, 1 H), 7.20 (d, J=8.3 Hz, 1 H), 7.58 (dd, J=5.4,0.6 Hz, 1 H), 7.60 (d, J=8.3 Hz, 1 H), 8.41 (d, J=5.3 Hz, 1 H), 8.75 (s,1 H)

EXAMPLE 4 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-5-fluoro-1H-benzo[d]imidazol-2(3H)-one6

Compound 6 was synthesized in the same manner as compound 1 usingintermediates 1-3 and 12-d as starting material. m/z=429 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.03 (m, 2 H), 0.98 (d, J=6.5Hz, 6 H), 1.09-1.17 (m, 2 H), 1.45-1.54 (m, 2 H), 1.65-1.69 (m, 1 H),2.84-2.89 (m, 1H), 4.34-4.42 (m, 2 H), 5.32 (s, 2 H), 6.78 (ddd, J=9.5,8.7, 2.4 Hz, 1 H), 7.07 (dd, J=8.7, 4.4 Hz, 1 H), 7.22 (d, J=8.3 Hz, 1H), 7.31 (dd, J=8.4, 2.4 Hz, 1 H), 7.59 (d, J=8.5 Hz, 1 H)

EXAMPLE 5 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one13

Compound 13 was synthesized in the same manner as compound 1 usingintermediates 1-3 and 13-d as starting material. m/z=411 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=6.8 Hz, 6 H), 0.99-1.05(m, 2 H), 1.10-1.17 (m, 2 H), 1.41-1.51 (m, 2 H), 1.63-1.73 (m, 1 H),2.84-2.92 (m, 1 H), 4.32-4.41 (m, 2 H), 5.37 (s, 2 H), 7.01-7.12 (m, 2H), 7.16-7.20 (m, 1 H), 7.22 (d, J=8.3 Hz, 1 H), 7.51-7.55 (m, 1 H),7.58 (d, J=8.5 Hz, 1 H)

EXAMPLE 6 Synthesis of4-(5-chloro-2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-imidazo[4,5-b]pyridin-1yl)butylpivalate 3

Step 1: Synthesis of (5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)methanol3-1

A mixture of intermediate 1-1 (14.5 g, 101 mmol) and 2-hydroxyaceticacid (16 g, 210 mmol) was stirred at 150° C. for 4 hours. The resultingmixture was cooled to 60° C. and treated with an aqueous solution of 3NHCl (70 mL), then basified to pH=7-8 by the addition of aqueous ammonia.The mixture was filtered and the solid was collected, washed with waterand methyl ter-butyl ether. The product 3-1 was collected as yellowpowder (17.5 g, 94%). m/z=184 (M+H)⁺.

Step 2: Synthesis of5-chloro-2-(trityloxymethyl)-1H-imidazo[4,5-b]pyridine 3-2

Intermediate 3-1 (17.5 g, 95.3 mmol) and triethylamine (28 mL, 190.6mmol) was dissolved in dichloromethane (300 mL). Then, trityl chloride(40 g, 143 mmol) was added. The resulting mixture was stirred at 25° C.for 1.5 h. The reaction mixture was washed with aqueous solution of 1Nhydrochloric acid and filtered. The solid was collected and washed withdichloromethane (500 mL). The filtrate was washed with aqueous solutionof 1N hydrochloric acid (200 mL), and with saturated aqueous solutionNaHCO₃ (200 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated to almost dryness under vacuum. The residue was filtered. Thesolid was collected and washed with dichloromethane. The product 3-2 wascollected (27 g, 68%). m/z=426 (M+H)⁺.

Step 3: Synthesis of4-(5-chloro-2-(trityloxymethyl)-1H-imidazo[4,5-b]pyridin-1-yl)butylpivalate 3-3

To the intermediate 3-2 (27 g, 63.4 mmol), 4-chlorobutyl pivalate (19 g,83.8 mmol), were added cesium carbonate (40 g, 122 mmol) and potassiumiodide (3 g, 18 mmol). The mixture was dissolved in DMF at 25° C. andthen warmed to 80° C. and stirred for 2 hours. The reaction mixture wascooled to 25° C., filtered and the filtrate was poured into ice-water.The mixture was extracted with ethyl acetate (2×500 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andevaporated under vacuum. The residue was purified by columnchromatography (Eluent: ethyl acetate:petroleum ether=1:3). Two isomerswere collected Compound 3-3 (5 g) and Compound 3-4 (20 g). m/z=582(M+H)⁺.

Step 4: Synthesis of4-(5-chloro-2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridin-1-yl)butylpivalate 3-5

The intermediate 3-3 (5 g, 8.6 mmol) was dissolved in CH₂Cl₂ (50 mL). Asolution of 4N HCl/dioxane (20 mL, 80 mmol) was added at 0° C. Themixture was stirred at 25° C. for 2 hours. The reaction mixture wasevaporated under vacuum at 40-45° C. The residue was co-evaporated withCH₂Cl₂ (70 mL). Dichloromethane (70 mL) was added to the residue. Themixture was filtered and the solid was collected and washed with methyltert-butyl ether. The hydrochloric salt of product 3-5 was collected asa white powder (2.83 g, 86%). This powder was dissolved in a mixture ofwater (50 mL) and dichloromethane (50 mL). Then sodium bicarbonate wasadded (1.02 g, 12 mmol) portionwise at 25° C., and the mixture wasstirred at 25° C. for overnight. The resulting mixture was extractedwith dichloromethane, dried over MgSO₄ and concentrated. The product 3-5was collected as a white solid. m/z=340 (M+H)⁺.

Step 5: Synthesis of4-(5-chloro-2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-imidazo[4,5-b]pyridin-1yl)butylpivalate 3

To a stirred solution of intermediate 3-5 (0.4 g, 1.16 mmol), triphenylphosphine (0.35 g, 1.34 mmol) and compound 10-d (0.214 g, 1.22 mmol) indry THF (30 mL) was added DIAD (94%, 0.264 mL, 1.34 mmol) dropwise atroom temperature. The reaction mixture was stirred overnight. After thecompletion of the reaction, the mixture was concentrated to dryness andthe residue was purified by column chromatography eluted with ethylacetate/CH₂Cl₂ then CH₂Cl₂/methanol to yield the title compound 3 as awhite solid (360 mg, 60%).

m/z=498 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97-1.04 (m, 2H),1.13-1.20 (m, 11 H), 1.66-1.85 (m, 4 H), 2.92 (tdd, J=6.9, 6.9, 3.8, 3.5Hz, 1 H), 4.08 (t, J=6.1 Hz, 2 H), 4.43 (t, J=7.3 Hz, 2 H), 5.38 (s, 2H), 7.13 (d, J=6.0 Hz, 1 H), 7.24 (d, J=8.5 Hz, 1 H), 7.64 (d, J=8.5 Hz,1 H), 8.35 (d, J=5.3 Hz, 1 H), 8.75 (d, J=0.5 Hz, 1 H)

EXAMPLE 7 Synthesis of3-((5-chloro-1-(4-hydroxybutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one14

Compound 3 (0.29 g, 0.58 mmol) was dissolved in THF (15 mL) and lithiumhydroxide (40 mg, 1.6 mmol) dissolved in water (5 mL) was added. Theresulting mixture was stirred at room temperature overnight. Thereaction mixture was poured in water and extracted with ethyl acetate.The organic layer was dried over MgSO₄ and concentrated. The residue waspurified by column chromatography using dichloromethane and methanol.The title compound 14 was isolated as a white powder (200 mg, 80%).m/z=414 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (m, J=2.8 Hz, 2 H), 1.09 (m, J=5.3Hz, 2 H), 1.39-1.51 (m, 2 H), 1.73 (quin, J=7.6 Hz, 2 H), 3.01 (tt,J=6.9, 3.5 Hz, 1 H), 3.39-3.45 (m, 2 H), 4.41 (t, J=7.4 Hz, 2 H), 5.47(s, 2 H), 7.31 (d, J=5.0 Hz, 1 H), 7.37 (d, J=8.5 Hz, 1 H), 8.18 (d,J=8.5 Hz, 1 H), 8.28 (d, J=5.3 Hz, 1 H), 8.41 (s, 1 H).

EXAMPLE 8 Synthesis of1-cyclopropyl-3-((1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one4

Step 1: Synthesis of (1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methanol4-3

The intermediate 4-3 was prepared in the same manner as the intermediate1-3 using pyridine-2,3-diamine 4-1 as starting material.

Step 2:1-cyclopropyl-3-((1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one4

Compound 4 was prepared in the same manner as compound 1 usingintermediates 4-3 and 13-d as starting material. m/z=376 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (d, J=6.5 Hz, 6 H), 0.99-1.06(m, 2 H), 1.10-1.19 (m, 2 H), 1.37-1.51 (m, 2 H), 1.69 (dquin, J=13.3,6.7, 6.7, 6.7, 6.7 Hz, 1 H), 2.89 (tt, J=6.9, 3.5 Hz, 1 H), 4.26-4.44(m, 2 H), 5.40 (s, 2 H), 7.06 (m, J=8.8, 7.5, 1.3 Hz, 2 H), 7.14-7.23(m, 2 H), 7.54 (dd, J=7.3, 1.3 Hz, 1 H), 7.62 (dd, J=8.0, 1.5 Hz, 1 H),8.54 (dd, J=4.8, 1.3 Hz, 1 H)

EXAMPLE 9 Synthesis of1-cyclopropyl-3-((1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one5

Compound 5 was prepared in the same manner as compound 4 usingintermediate 10-d as starting material. m/z=377 (M+H)⁺.

¹H NMR (360 MHz, CHLOROFORM-d) δ ppm 1.01 (m, 2 H), 0.99 (d, J=6.6 Hz, 6H), 1.13-1.21 (m, 2 H), 1.44-1.56 (m, 2 H), 1.62-1.77 (m, 1 H),2.87-2.96 (m, 1 H), 4.30-4.40 (m, 2 H), 5.41 (s, 2 H), 7.13 (d, J=5.5Hz, 1 H), 7.21 (dd, J=8.1, 4.8 Hz, 1 H), 7.65 (d, J=7.7 Hz, 1 H), 8.33(d, J=5.5 Hz, 1 H), 8.54 (d, J=4.8 Hz, 1 H), 8.70 (s, 1H)

EXAMPLE 10 Synthesis of1-cyclopropyl-5-fluoro-3-((1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one8

Compound 8 was prepared in the same manner as compound 4 usingintermediate 12-d as starting material. m/z=394 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=6.8 Hz, 6 H), 0.99-1.04(m, 2 H), 1.08-1.18 (m, 2 H), 1.39-1.56 (m, 2 H), 1.60-1.74 (m, 1 H),2.77-2.97 (m, 1 H), 4.25-4.46 (m, 2 H), 5.35 (s, 2 H), 6.78 (m, J=9.0,2.0 Hz, 1 H), 7.07 (dd, J=8.7, 4.4 Hz, 1 H), 7.20 (dd, J=8.3, 4.8 Hz, 1H), 7.34 (dd, J=8.4, 2.4 Hz, 1 H), 7.64 (dd, J=8.0, 1.5 Hz, 1 H), 8.55(dd, J=4.8, 1.5 Hz, 1 H)

EXAMPLE 11 Synthesis of3-((1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(oxetan-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one9

Compound 9 was prepared in the same manner as compound 4 usingintermediate 11-d as starting material. m/z=393 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.98 (d, J=6.8 Hz, 6 H), 1.48-1.59(m, 2 H), 1.62-1.77 (m, 1 H), 4.26-4.39 (m, 2 H), 5.06-5.19 (m, 4 H),5.43 (s, 2 H), 5.58-5.69 (m, 1 H), 7.21 (dd, J=8.3, 4.8 Hz, 1 H), 7.58(d, J=5.3 Hz, 1 H), 7.65 (dd, J=8.0, 1.5 Hz, 1 H), 8.42 (d, J=5.3 Hz, 1H), 8.55 (dd, J=4.8, 1.5 Hz, 1 H), 8.81 (s, 1 H).

EXAMPLE 12 Synthesis of1-cyclopropyl-3-((1-(3-(methylsulfonyl)propyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one7

Step 1: Synthesis of N-(3-methylsulfonyl)propyl)-2-nitropyridin-3-amine7-1

3-Fluoro-2-nitropyridine (0.7 g, 4.92 mmol, CAS 54231-35-5) wasdissolved in DMF (30 mL). Then, 3-(methylsulfonyl)propan-1-aminehydrochloride 6-e (0.9 g, 5.2 mmol) was added followed by triethylamine(1.5 mL, 11.3 mmol). The resulting mixture was stirred at roomtemperature overnight. The mixture was poured in water and extractedwith dichloromethane, dried over MgSO₄ and concentrated. The residue waspurified by column chromatography using ethyl acetate to yield theintermediate 7-1 as an orange solid (1.2 g, 93%).

m/z=260 (M+H)⁺.

Step 2: Synthesis of N³-(3-methylsulfonyl)propyl)pyridine-2,3-diamine7-2

Intermediate 7-1 (1.2 g, 4.62 mmol) in THF (300 mL) was hydrogenated at20° C. with wet 10% Pd/C (0.5 g) as a catalyst overnight. After uptakeof H₂ (3 eq), the catalyst was filtered off and the filtrate wasevaporated. The residue was washed with methyl ter-butyl ether to affordthe title compound 7-2 as a light yellow powder (1 g, 94%).

m/z=230 (M+H)⁺.

Step 3: Synthesis of(1-(3-(methylsulfonyl)propyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 7-3

A mixture of intermediate 7-2 (1 g, 4.36 mmol) and methyl2-hydroxyacetate (2 mL, 26 mmol) was stirred at 130° C. overnight. Theresulting mixture was allowed to cool down to room temperature anddiluted with dichloromethane. The resulting mixture was poured in waterand extracted with dichloromethane. The organic layer was dried overMgSO₄ filtered and concentrated. The water layer was evaporated thenboth residues were mixed and purified by column chromatographydichloromethane/methanol. The product 7-3 was collected as a whitepowder (0.43 g, 36%). m/z=270 (M+H)⁺.

Step 4: Synthesis of1-cyclopropyl-3-((1-(3-(methylsulfonyl)propyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one7

Compound 7 was prepared in the same manner as compound 1 usingintermediates 7-3 and 10-d as starting material. m/z=427 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.89-0.97 (m, 2 H), 1.03-1.12 (m, 2 H),2.10-2.25 (m, 2 H), 3.00 (s, 3 H), 2.93-3.05 (m, 1 H), 3.19-3.27 (m, 2H), 4.52 (t, J=7.4 Hz, 2 H), 5.48 (s, 2 H), 7.29 (m, J=5.0 Hz, 2 H),8.10 (dd, J=8.0, 1.5 Hz, 1 H), 8.27 (d, J=5.3 Hz, 1 H), 8.38 (dd, J=4.8,1.5 Hz, 1 H), 8.45 (s, 1 H)

EXAMPLE 13 Synthesis of1-cyclopropyl-3-((1-(3-(methoxypropyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one10

Step 1: Synthesis of N³-(3-methoxypropyl)pyridine-2,3-diamine 10-2

The intermediate 10-2 was prepared in the same manner as intermediate7-2 using 3-methoxypropan-1-amine as starting material.

Step 2: Synthesis of2-(diethoxymethyl)-1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyridine 10-3

Intermediate 10-2 (10 g, 34.43 mmol) was dissolved in ethanol (70 mL).Then ethyl 2,2-diethoxyacetate (7.39 mL, 41.3 mmol) and sodiumethanolate (14.14 mL, 37.8 mmol) were added. The resulting mixture wasrefluxed for 4 days. The dark solution was allowed to cool down to roomtemperature then the solvent was removed under vacuum. The residue wasdissolved in water (300 mL) and dichloromethane was added. The mixturewas extracted with dichloromethane. The combined organic layers weredried over Na₂SO₄, filtered and evaporated. The residue was purified bycolumn chromatography eluting with ethyl acetate/dichloromethane. Theintermediate 10-3 was collected (5.15 g, 48%). m/z=294 (M+H)⁺.

Step 3: Synthesis of1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyridine-2-carbaldehyde 10-4

A solution of intermediate 10-3 (5.15 g, 17.55 mmol) in an aqueoussolution of 1N hydrochloric acid (79 mL, 79 mmol) was stirred at 60° C.for 2 days. The resulting mixture was allowed to cool down to roomtemperature then ethyl acetate and water were added. A saturatedsolution of Na₂CO₃ was added to adjust the pH to basic and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and evaporated under vacuum. Compound10-4 was collected as a brown dark oil (3 g, 76%).

Step 4: Synthesis of1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 10-5

To a solution of intermediate 10-4 (3 g, 10.4 mmol) in THF (40 mL) andmethanol (40 mL) sodium borohydride (0.8 g, 21 mmol) was addedportionwise at 0° C. The resulting mixture was stirred at roomtemperature overnight. The solvent was removed then the residue wasdissolved in ethyl acetate (50 mL), water was added (100 mL). Theresulting mixture was extracted with ethyl acetate (3×50 mL). Theseparated organic layer was washed with brine, dried over Na₂SO₄,filtered and evaporated under vacuum. The residue was purified by columnchromatography using dichloromethane/methanol. The title compound wascollected as an orange oil (1 g, 42%). m/z=222 (M+H)⁺.

Step 5: Synthesis of1-cyclopropyl-3-((1-(3-(methoxypropyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one10

Compound 10 was prepared in the same manner as compound 1 usingintermediates 10-5 and 10-d as starting material m/z=379 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88-0.97 (m, 2 H), 1.03-1.14 (m, 2 H),1.99 (quin, J=6.3 Hz, 2 H), 3.00 (tt, J=6.8, 3.6 Hz, 1 H), 3.23 (s, 3H), 3.29 (t, J=5.9 Hz, 2 H), 4.44 (t, J=6.8 Hz, 2 H), 5.46 (s, 2 H),7.26 (dd, J=8.0, 4.8 Hz, 1 H), 7.30 (d, J=5.3 Hz, 1 H), 7.97-8.06 (m, 1H), 8.27 (d, J=5.3 Hz, 1 H), 8.33-8.39 (m, 1 H), 8.41 (s, 1 H).

EXAMPLE 14 Synthesis of3-((1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(oxetan-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one12

Compound 12 was prepared in the same manner as compound 10 usingintermediate 11-d as starting material m/z=395 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.01 (quin, J=6.3 Hz, 2 H), 3.23 (s, 3H), 3.30 (t, J=1.0 Hz, 2 H), 4.45 (t, J=6.9 Hz, 2 H), 4.93-5.04 (m, 2H), 5.09 (t, J=6.7 Hz, 2 H), 5.50 (s, 2 H), 5.53-5.64 (m, 1 H), 7.26(dd, J=8.0, 4.8 Hz, 1 H), 7.55 (d, J=5.3 Hz, 1 H), 8.02 (dd, J=8.0, 1.3Hz, 1 H), 8.32 (d, J=5.3 Hz, 1 H), 8.36 (dd, J=4.8, 1.3 Hz, 1 H), 8.50(s, 1 H).

EXAMPLE 15 Synthesis of1-cyclopropyl-5-fluoro-3-((1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one15

Compound 15 was prepared in the same manner as compound 10 usingintermediate 12-d as starting material m/z=396 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84-0.95 (m, 2 H), 1.01-1.13 (m, 2 H),1.97 (m, J=6.3, 6.3, 6.3, 6.3 Hz, 2 H), 2.94 (m, J=6.8, 6.8, 3.5, 3.5Hz, 1 H), 3.23 (s, 3 H), 3.25-3.29 (m, 2 H), 4.43 (t, J=6.9 Hz, 2 H),5.38 (s, 2 H), 6.84-6.99 (m, 1 H), 7.17 (dd, J=9.2, 2.4 Hz, 1 H), 7.22(dd, J=1.0 Hz, 1 H), 7.26 (dd, J=1.0 Hz, 1 H), 8.00 (dd, J=8.0, 1.3 Hz,1 H), 8.36 (dd, J=4.5, 1.3 Hz, 1 H).

EXAMPLE 16 Synthesis of1-cyclopropyl-3-((1-(3-(fluoropropyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one11

The intermediate 11-5 was prepared in the same manner as intermediate10-5 using 3-fluoropropan-1-amine hydrochloride (CAS 64068-31-1) and3-fluoro-2-nitropyridine (CAS 54231-35-35) as starting materials.

Compound 11 was prepared in the same manner as compound 10 usingintermediates 11-5 and 10-d as starting material m/z=337 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88-0.97 (m, 2 H), 1.02-1.11 (m, 2 H),2.06-2.26 (m, 2 H), 3.00 (dt, J=6.9, 3.3 Hz, 1 H), 4.39-4.63 (m, 4 H),5.46 (s, 2 H), 7.27 (dd, J=8.2, 4.6 Hz, 1 H), 7.30 (d, J=5.3 Hz, 1 H),8.04 (dd, J=8.0, 1.5 Hz, 1 H), 8.27 (d, J=5.3 Hz, 1 H), 8.37 (dd, J=4.8,1.5 Hz, 1 H), 8.41 (s, 1 H).

EXAMPLE 17 Synthesis of3-((6-bromo-3-isopentyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one16

Intermediate 16-5 was prepared following the 5 steps synthesis reportedfor intermediate 10-5 using 5-bromo-2-chloro-3-nitropyridine (CAS67443-38-3) and 3-methylbutane-1-amine (CAS 107-85-7) as startingmaterial.

Compound 16 was prepared in the same manner as compound 10 usingintermediates 16-5 and 10-d as starting material. m/z=456 (M+H)⁺.

¹H NMR (360 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=6.6 Hz, 6 H), 0.99-1.07(m, 2 H), 1.18-1.21 (m, 2 H), 1.54-1.62 (m, 2 H), 1.68 (tt, J=13.3, 6.6Hz, 1 H), 2.93 (tdd, J=6.9, 6.9, 3.7, 3.5 Hz, 1 H), 4.39 (m, J=8.1 Hz, 2H), 5.36 (s, 2 H), 7.16 (dd, J=5.1, 0.7 Hz, 1 H), 8.15 (d, J=2.2 Hz, 1H), 8.34 (d, J=5.1 Hz, 1 H), 8.41 (d, J=1.8 Hz, 1 H), 8.57 (d, J=0.7 Hz,1 H).

EXAMPLE 18 Synthesis of3-((6-bromo-3-isopentyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(oxetan-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one18

Compound 18 was prepared in the same manner as compound 16 usingintermediates 16-5 and 11-d as starting material m/z=472 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (d, J=6.5 Hz, 6 H), 1.50-1.61(m, 2 H), 1.67 (m, J=6.5 Hz, 1 H), 4.26-4.49 (m, 2 H), 5.02-5.24 (m, 4H), 5.38 (s, 2 H), 5.65 (tdd, J=7.6, 7.6, 5.9, 5.8 Hz, 1 H), 7.61 (d,J=5.3 Hz, 1 H), 8.14 (d, J=2.0 Hz, 1 H), 8.31-8.50 (m, 2 H), 8.66 (s, 1H)

EXAMPLE 19 Synthesis of1-((6-bromo-3-isopentyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one30

Compound 30 was prepared in the same manner as compound 16 usingintermediates 16-5 and 13-d as starting material m/z=455 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94 (d, J=6.5 Hz, 6 H), 1.00-1.07(m, 2 H), 1.14 (m, J=7.3, 1.5 Hz, 2 H), 1.41-1.54 (m, 2 H), 1.66 (m,J=13.4, 6.6, 6.6, 6.6 Hz, 1 H), 2.90 (tdd, J=6.9, 6.9, 3.8, 3.5 Hz, 1H), 4.32-4.46 (m, 2 H), 5.34 (s, 2 H), 7.03 (m, J=7.7, 1.4 Hz, 1 H),7.09 (td, J=7.7, 1.3 Hz, 1 H), 7.20 (dd, J=7.7, 0.6 Hz, 1 H), 7.28 (dd,J=7.7, 0.6 Hz, 1 H), 8.15 (d, J=2.0 Hz, 1 H), 8.40 (d, J=2.0 Hz, 1 H)

EXAMPLE 20 Synthesis of1-cyclopropyl-3-((3-isopentyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one24

To intermediate 16 (0.49 g, 1.09 mmol) in methanol (30 mL) were addedpotassium acetate (0.128 g, 1.3 mmol), thiophenol (0.5 mL) and wet 10%Pd/C (0.2 g). The reaction mixture was stirred at 25° C. under hydrogenatmosphere. After uptake of H₂ (1 eq), the catalyst was filtered off andthe filtrate was evaporated. The residue was dissolved in water anddichloromethane. The resulting mixture was successively extracted withdichloromethane dried over MgSO₄ and concentrated. The residue waspurified by column chromatography using dichloromethane/ methanol. Thetitle compound 24 was collected as a white powder (333 mg, 81%). m/z=377(M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=6.8 Hz, 6 H), 1.03-1.06(m, 2 H), 1.15-1.21 (m, 2 H), 1.51-1.60 (m, 2 H), 1.67-1.71 (m, 1 H),2.9-2.95 (m, 1 H), 4.37-4.44 (m, 2 H), 5.38 (s, 1 H), 7.14 (dd, J=5.3,0.8 Hz, 1 H), 7.22 (dd, J=8.0, 4.8 Hz, 1 H), 8.02 (dd, J=8.2, 1.4 Hz, 1H), 8.33 (d, J=5.3 Hz, 1 H), 8.38 (dd, J=4.8, 1.5 Hz, 1 H), 8.58 (s, 1H)

EXAMPLE 21 Synthesis of methyl2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-3-isopentyl-3H-imidazo[4,5-b]pyridine-6-carboxylate26

The mixture of compound 16 (1 g, 2.15 mmol), palladium acetate (9.8 mg,0.043 mmol), 1,3-bis(diphenylphosphino)propane (35.4 mg, 0.086 mmol),potassium acetate (316 mg, 3.22 mmol) and methanol (10 mL) in THF (100mL) was charged in an autoclave under nitrogen atmosphere.

The autoclave was closed and pressurized to 20 bar of carbon monoxideand the reaction was carried out for 16 hours at 125° C. The reactionmixture was allowed to cool down to room temperature and filtered overan acrodisk. The solvent was evaporated and the residue was purified bycolumn chromatography using ethyl acetate/ methanol. The title compound26 was collected as a white powder (870 mg, 91%). m/z=435 (M+H)⁺.

¹H NMR (360 MHz, CHLOROFORM-d) δ ppm 0.98 (d, J=6.6 Hz, 6 H), 1.18 (m,J=5.9 Hz, 2 H), 1.52-1.61 (m, 2 H), 1.61-1.78 (m, 1 H), 2.93 (tdd,J=6.9, 6.9, 3.7, 3.5 Hz, 1 H), 3.97 (s, 3 H), 4.35-4.50 (m, 2 H), 5.39(s, 2 H), 7.16 (d, J=5.1 Hz, 1 H), 8.35 (d, J=5.1 Hz, 1 H), 8.58 (s, 1H), 8.64 (d, J=1.8 Hz, 1 H), 9.06 (d, J=1.8 Hz, 1 H)

EXAMPLE 22 Synthesis of2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-3-isopentyl-3H-imidazo[4,5-b]pyridine-6-carboxylicacid 28

Compound 26 (0.84 g, 1.89 mmol) was dissolved in THF (15 mL) and lithiumhydroxide (544 mg, 22.7 mmol) dissolved in water (10 mL) was added. Theresulting mixture was stirred at room temperature overnight. The pH ofthe resulting mixture was adjusted to pH=4 by addition of a 1 M solutionof hydrochloric acid. Then the mixture was extracted with ethyl acetate.The organic layer was dried over MgSO₄ and concentrated. The titlecompound 28 was isolated as a white powder (690 mg, 84%).

m/z=421 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (d, J=5.8 Hz, 8 H), 1.081-1.12 (m,2 H), 1.60-1.65 (m, 3 H), 3.00 (br. s., 1 H), 4.40-4.45 (m, 2 H), 5.48(s, 2 H), 7.30 (d, J=5.3 Hz, 2 H), 8.27 (d, J=5.0 Hz, 1 H), 8.39 (s, 1H), 8.43 (d, J=1.3 Hz, 1 H), 8.91 (d, J=1.3 Hz, 1 H)

EXAMPLE 23 Synthesis of2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-3-isopentyl-3H-imidazo[4,5-b]pyridine-6-carbonitrile27

The mixture of compound 16 (0.5 g, 1 mmol),Dichloro(diphenylphosphinoferrocene)palladium (78.7 mg, 0.108 mmol),dicyanozinc (0.505 g, 4.3 mmol) and triethyl amine (0.6 mL, 4.3 mmol) indioxane (10 mL) under nitrogen atmosphere was irradiated for 1 h in amicrowave reactor at 125° C. The resulting mixture was allowed to cooldown to room temperature then filtered over dicalite. The filtrate wasevaporated to dryness. The pεσιδνε was purified by column chromatographyusing EtOAc/MeOH 8-2. The title compound 27 was isolated as a whitesolid (200 mg, 45%). m/z=402 (M+H)⁺.

¹H NMR (360 MHz, CHLOROFORM-d) δ ppm 0.95-1.08 (m, 2 H), 1.03 (d, J=6.2Hz, 6 H), 1.17-1.29 (m, 3 H), 1.64-1.80 (m, 2 H), 2.91-3.05 (m, 1 H),4.38-4.49 (m, 2 H), 5.44 (s, 2 H), 7.27-7.31 (m, 1 H), 8.17-8.33 (m, 1H), 8.49-8.58 (m, 1 H), 8.62 (d, J=1.8 Hz, 1 H), 8.89-8.99 (m, 1 H)

EXAMPLE 24 Synthesis of3-((6-(aminomethyl)-3-isopentyl-3H-imidazo[4,5-b]pyridine-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one17

Compound 27 (125 mg, 0.31 mmol) in methanol/NH₃ (100 mL) washydrogenated at 20° C. with Raney Nickel (50 mg) as a catalystovernight. After uptake of H₂ (2 eq), the catalyst was filtered off andthe filtrate was evaporated. The residue was purified by columnchromatography using dichloromethane/MeOH/NH₃. The title compound 17 wasisolated as a white solid (25.5 mg, 20%). m/z=406 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92 (d, J=6.3 Hz, 8 H), 1.03-1.13 (m, 2H), 1.45-1.69 (m, 3 H), 2.99 (tdd, J=7.0, 7.0, 3.6, 3.5 Hz, 1 H), 3.81(s, 2 H), 4.26-4.41 (m, 2 H), 5.42 (s, 2 H), 7.29 (dd, J=5.3, 0.8 Hz, 1H), 7.96 (d, J=2.0 Hz, 1 H), 8.25 (d, J=5.3 Hz, 1 H), 8.30 (d, J=2.0 Hz,1 H), 8.37 (s, 1 H)

EXAMPLE 25 Synthesis of2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-3-isopentyl-3H-imidazo[4,5-b]pyridin-6-ylboronicacid 23

The mixture of compound 16 (0.5 g, 1 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (0.382 g, 1.5mmol) and potassium acetate (0.16 g, 1.6 mmol) in dioxane (20 mL) underargon atmosphere was stirred at room temperature for 10 minutes. To theresulting mixture dichloro(diphenylphosphinoferrocene)palladium (39 mg,0.05 mmol) was added. The resulting mixture was warmed to 115° C. for 3hours. The mixture was allowed to cool down to room temperature then thesolvent was removed. The residue (23-1) was dissolved in acetonitrile(40 mL) and an aqueous solution of hydrochloric acid 6 M (1.7 mL, 10mmol) was added. The resulting mixture was stirred at 110° C. for 2hours. The mixture was allowed to cool down to room temperature andwater (30 mL) was added the pH was adjusted to pH=7 by addition of asolution 7N of ammoniac in methanol. The resulting mixture wasconcentrated and the residue was purified by preparative HPLC. The titlecompound 23 was isolated as a white solid (309 mg, 67%). m/z=421 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92 (d, J=6.5 Hz, 8 H), 1.08-1.16 (m, 2H), 1.47-1.71 (m, 3 H), 2.99 (tdd, J=7.0, 7.0, 3.6, 3.5 Hz, 1 H), 4.35(m, J=7.8 Hz, 2 H), 5.43 (s, 2 H), 7.29 (d, J=5.0 Hz, 1 H), 8.21 (s, 2H), 8.25 (d, J=5.3 Hz, 1 H), 8.32 (d, J=1.5 Hz, 1 H), 8.38 (s, 1 H),8.68 (d, J=1.5 Hz, 1 H)

EXAMPLE 26 Synthesis of3-((6-bromo-3-(4-hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one19

Step 1: Synthesis of5-bromo-N-(4-(tert-butyldiphenylsilyloxy)butyl)-3-nitropyridin-2amine19-1

A mixture of 5-bromo-2-chloro-3-nitropyridine (CAS 67443-38-3) (33 g,101 mmol), 4-(tert-butyldiphenylsilyloxy)butan-1-amine 8-b (20 g, 84.2mmol), potassium carbonate (23.3 g, 168 mmol) and potassium iodide (1.4g, 8.4 mmol) in CH₃CN (200 mL) was stirred at 20° C. for 15 h. Theresulting mixture was treated with CH₂Cl₂ (400 mL) and water (400 mL).The separated aqueous layer was extracted with CH₂Cl₂ (2×200 mL). Thecombined organic layers were washed with brine (400 mL), dried overNa₂SO₄, filtered and evaporated under vacuum. The intermediate 19-1 wasobtained (44 g, 90%). m/z=530 (M+H)⁺.

Step 2: Synthesis of5-bromo-N²-(4-(tert-butyldiphenylsilyloxy)butyl)pyridine-2,3-diamine19-2

Intermediate 19-1 (48 g, 84 mmol) was dissolved in acetic acid (270 mL)and water (25 mL). The resulting mixture was warmed to 50° C. Iron (Fe)(36.1 g, 647 mmol) was added very slowly to the mixture in 20 min. Themixture was stirred at 50° C. for 2 h and allowed to cool down to roomtemperature. Water (400 mL) was added and the mixture was filteredthrough a celite pad. The residue collected on the filter was washedwith water. The filtrate was treated with ethyl acetate (2×300 mL). Theorganic layer was separated and washed with water (2×400 mL) and brine(500 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated under vacuum. The residue was co-evaporated with tolueneunder vacuum to give intermediate 19-2 (40 g, 90%).

Step 3, 4 and 5: Synthesis of(6-bromo-3-(4-(tert-butyldiphenylsilyloxy)butyl)-3H-imidazo[4,5-b]pyridin-2-yl)methanol19-5

Intermediate 19-5 was prepared in the same manner as intermediate 10-5in 3 steps synthesis starting from intermediate 19-2

Step 6: Synthesis of3-((6-bromo-3-(4-(tert-butyldiphenylsilyloxy)butyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one19-6

The intermediate 19-6 was prepared in the same manner as compound 10using intermediates 19-5 and 10-d as starting material m/z=696 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94-1.05 (m, 11 H), 1.13-1.21 (m,2 H), 1.51-1.58 (m, 2 H), 1.73-1.91 (m, 2 H), 2.87 (tdd, J=6.9, 6.9,3.8, 3.5 Hz, 1 H), 3.63 (t, J=6.1 Hz, 2 H), 4.42 (t, J=7.5 Hz, 2 H),5.31 (s, 2 H), 7.09 (dd, J=5.3, 0.5 Hz, 1 H), 7.30-7.36 (m, 4 H), 7.38(m, J=7.3 Hz, 2 H), 7.55-7.65 (m, 4 H), 8.15 (d, J=2.0 Hz, 1 H), 8.33(d, J=5.3 Hz, 1 H), 8.38 (d, J=2.3 Hz, 1 H), 8.58 (s, 1 H)

Step 7: Synthesis of3-((6-bromo-3-(4-hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one19

The intermediate 19-6 (1.65 g, 2.32 mmol) was dissolved in methanol (40mL), then ammonium fluoride (0.206 g, 5.58 mmol) was added. Theresulting mixture was stirred at reflux for 56 hours. The reactionmixture was allowed to cool down to room temperature, then the solventwas removed. The residue was purified by column chromatography usingdichloromethane/methanol to yield the product as a white solid (1 g,92%). m/z=458 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87-0.96 (m, 2 H), 1.07 (m, J=2.0 Hz, 2H), 1.37-1.51 (m, 2 H), 1.69-1.83 (m, 2 H), 3.00 (tdd, J=7.0, 7.0, 3.6,3.5 Hz, 1 H), 3.35-3.44 (m, 2 H), 4.37 (t, J=7.5 Hz, 2 H), 4.44 (t,J=5.1 Hz, 1 H), 5.45 (s, 2 H), 7.29 (dd, J=5.3, 0.8 Hz, 1 H), 8.26 (d,J=5.3 Hz, 1 H), 8.32 (d, J=2.0 Hz, 1 H), 8.37 (d, J=0.5 Hz, 1 H), 8.44(d, J=2.0 Hz, 1 H)

EXAMPLE 27 Synthesis of3-((6-bromo-3-(4-hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(oxetan-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one20

Step 1: Synthesis of3-((6-bromo-3-(4-(tert-butyldiphenylsilyloxy)butyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(oxetan-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one20-1

Intermediate 20-1 was prepared in the same manner as intermediate 19-6using intermediates 19-5 and 11-d as starting material. m/z=712 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.01 (s, 9 H), 1.56 (s, 2 H), 1.86(m, J=7.6, 7.6, 7.6, 7.6 Hz, 2 H), 3.64 (t, J=6.1 Hz, 2 H), 4.40 (t,J=7.4 Hz, 2 H), 5.03-5.13 (m, 4 H), 5.33 (s, 2 H), 5.51-5.63 (m, 1 H),7.31-7.37 (m, 4 H), 7.39 (d, J=7.0 Hz, 2 H), 7.54-7.58 (m, 1 H), 7.61(dd, J=8.0, 1.5 Hz, 4 H), 8.15 (d, J=2.0 Hz, 1 H), 8.39 (d, J=2.0 Hz, 1H), 8.41 (d, J=5.3 Hz, 1 H), 8.66 (s, 1 H)

Step 2: Synthesis of3-((6-bromo-3-(4-hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(oxetan-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one20

Compound 20 was prepared in the same manner as compound 19 usingintermediates 20-1 as starting material m/z=474 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56-1.67 (m, 2 H), 1.86 (qd,J=7.6, 7.4 Hz, 2 H), 2.22 (br. s, 1 H), 3.69 (t, J=6.0 Hz, 2 H),4.38-4.51 (m, 2 H), 5.04-5.21 (m, 4 H), 5.40 (s, 2 H), 5.62 (tt, J=7.7,5.8 Hz, 1 H), 7.61 (dd, J=5.4, 0.6 Hz, 1 H), 8.16 (d, J=2.3 Hz, 1 H),8.32-8.49 (m, 2 H), 8.73 (d, J=0.5 Hz, 1 H)

EXAMPLE 28 Synthesis of3-((6-chloro-3-(4-hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one21

Step 1: Synthesis of3-((3-(4-(tert-butyldiphenylsilyloxy)butyl)-6-chloro-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one21-2

Intermediate 21-1 was prepared in the same manner as intermediate 19-5in 5 steps synthesis using 2,5-dichloro-3-nitropyridine (CAS 21427-62-3)as starting material. Intermediate 21-2 was prepared in the same manneras intermediate 19-6 using intermediates 21-1 and 10-d as startingmaterial

m/z=652 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97-1.04 (m, 11 H), 1.13-1.21 (m,2 H), 1.46-1.64 (m, 2 H), 1.82-1.91 (m, 2 H), 2.88 (tdd, J=7.0, 7.0,3.6, 3.5 Hz, 1 H), 3.63 (t, J=6.1 Hz, 2 H), 4.43 (t, J=7.4 Hz, 2 H),5.31 (s, 2 H), 7.09 (d, J=5.3 Hz, 1 H), 7.29-7.36 (m, 4 H), 7.38 (m,J=7.3 Hz, 2 H), 7.60 (dd, J=7.9, 1.4 Hz, 4 H), 8.00 (d, J=2.0 Hz, 1 H),8.30 (d, J=2.0 Hz, 1 H), 8.33 (d, J=5.3 Hz, 1 H), 8.59 (s, 1 H)

Step 2: Synthesis of3-((6-chloro-3-(4-hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one21

Compound 21 was prepared in the same manner as compound 19 usingintermediates 21-2 as starting material. m/z=414 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.98-1.06 (m, 2 H), 1.17-1.21 (m, 2H), 1.64-1.68 (m, 2 H), 1.84-1.91 (m, 2 H), 2.36-2.41 (m, 1 H),2.95-3.01 (tdd, J=7.0, 7.0, 3.6, 3.5 Hz, 1 H), 3.71 (q, J=5.9 Hz, 2 H),4.41-4.50 (m, 2 H), 5.37 (s, 2H), 7.15 (dd, J=5.3, 0.8 Hz, 1 H), 8.02(d, J=2.0 Hz, 1 H), 8.32 (d, J=2.0 Hz, 1 H), 8.35 (d, J=5.3 Hz, 1 H),8.66 (d, J=0.8 Hz, 1 H)

EXAMPLE 29 Synthesis of1-cyclopropyl-3-((6-fluoro-3-(4-hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one22

Step 1: Synthesis of5-fluoro-3-nitropyridin-2-yl4-methylbenzenesulfonate 22-1

To a mixture of 5-fluoro-3-nitropyridin-2-ol (24.2 g, 153 mmol, CAS136888-20-3), tosyl-chloride (33.4 g, 176 mmol) in dichloromethane (1000mL) was added at room temperature, under nitrogen atmosphere, triethylamine (44 mL, 304 mmol). At the end of the addition, DMAP (3.7 g, 30mmol) was added. The resulting mixture was stirred at 25° C. for 16 h.Dichloromethane (500 mL) was added and the mixture was successivelywashed with an aqueous solution 1N of hydrochloric acid (2×500 mL) andbrine (500 mL). The separated aqueous layer was extracted with CH₂Cl₂(400 mL). The combined organic layers were dried over Na₂SO₄ andfiltered through a silica pad (50 g). The filtrate was purified by flashchromatography (eluent: CH₂Cl₂) to give intermediate 22-1 (34 g, 67%).

Step 2: Synthesis ofN-(4-(tert-butyldiphenylsilyloxy)butyl)-5-fluoro-3-nitropyridin-2-amine22-2

Intermediate 22-2 was prepared in the same manner as intermediate 19-1using intermediates 22-1 and 8-b as starting material

Steps 3,4,5,6 and 7: synthesis of3-((3-(4-(tert-butyldiphenylsilyloxy)butyl)-6-fluoro-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one22-7

Intermediate 22-7 was prepared in the same manner as intermediate 19-5in 5 steps synthesis using intermediate 22-2 as starting material.m/z=635 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.12 (m, 2H),1.00 (s, 9 H), 1.09-1.17 (m, 2 H), 1.52-1.64 (m, 2 H), 1.76-1.89 (m, 2H), 2.88 (tdd, J=7.0, 7.0, 3.6, 3.5 Hz, 1H), 3.64 (t, J=6.3 Hz, 2 H),4.43 (t, J=7.4 Hz, 2 H), 5.31 (s, 2 H), 7.09 (dd, J=5.3, 0.8 Hz, 1 H),7.30-7.42 (m, 6 H), 7.58-7.64 (m, 4 H), 7.72 (dd, J=8.7, 2.6 Hz, 1 H),8.24 (dd, J=2.5, 1.8 Hz, 1 H) 8.33 (d, J=5.3 Hz, 1 H), 8.60 (s, 1 H)

Step 8: Synthesis of1-cyclopropyl-3-((6-fluoro-3-(4-hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one22

Compound 22 was prepared in the same manner as compound 19 usingintermediate 22-7 as starting material. m/z=397 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.07 (m, 2 H), 1.14-1.21 (m, 2H), 1.65 (quin, J=6.6 Hz, 2 H), 1.85 (qd, J=7.5, 7.3 Hz, 2 H), 2.48 (t,J=5.3 Hz, 1 H), 2.95 (tdd, J=7.0, 7.0, 3.6, 3.5 Hz, 1 H), 3.71 (m, J=4.0Hz, 2 H), 4.41-4.51 (m, 2 H), 5.37 (s, 2 H), 7.15 (dd, J=5.3, 0.8 Hz, 1H), 7.74 (dd, J=8.5, 2.5 Hz, 1 H), 8.26 (dd, J=2.5, 1.8 Hz, 1 H), 8.34(d, J=5.5 Hz, 1 H), 8.66 (d, J=0.5 Hz, 1 H)

EXAMPLE 30 Synthesis of4-chloro-3-((3-isopentyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one25

Step 1: Synthesis of N-isopentyl-3-nitropyridin-2-amine 25-1

Intermediate 25-1 was prepared in the same manner as intermediate 7-1using the commercially available 2-chloro-3-nitropyridine (CAS5470-18-8) and isopentylamine (CAS 107-85-7). m/z=210 (M+H)⁺.

Step 2: Synthesis of N²-isopentylpyridine-2,3-diamine 25-2

Intermediate 25-2 was prepared in the same manner as intermediate 7-2using intermediates 25-1 as starting material m/z=178 (M+H)⁺.

Step 3: Synthesis of3-isopentyl-2-(trichloromethyl)-3H-imidazo[4,5-b]pyridine 25-3

Intermediate 25-2 (17.5 g, 97.6 mmol) was dissolved in acetic acid (220mL). To the resulting mixture methyl 2,2,2-trichloroacetimidate (CAS2533-69-9) (12.13 mL, 97.6 mmol) was added at once. The resultingmixture was stirred at 50° C. for 48 h. The mixture was allowed to coolto room temperature and poured onto ice/water solution. The pH wasadjusted to pH=5 by addition of sodium carbonate. The resulting mixturewas extracted with dichloromethane (3×100 mL). The combined organiclayers were successively washed with saturated NaHCO₃, dried over MgSO₄and evaporated. The residue was purified by column chromatography usingCH₂Cl₂ to CH₂Cl₂/EtOAc as the eluent to give an oil which solidified ondrying in vacuo (23 g, 77%). m/z=307 (M+H)⁺.

Step 4: Synthesis of methyl3-isopentyl-3H-imidazo[4,5-b]pyridine-2-carboxylate 25-4

Intermediate 25-3 (20 g, 65.22 mmol) was dissolved in MeOH (400 mL) andsodium carbonate (6.9 g, 65.22 mmol) was added. The resulting mixturewas stirred at room temperature for 1 hour and sodium methanolate (25%,6 mL, 26.1 mmmol) was added. The resulting mixture was refluxed for 48hours. The mixture was allowed to cool to room temperature and filtered.The filtrate was evaporated to dryness. The residue was purified bycolumn chromatography using CH₂Cl₂ to CH₂Cl₂/EtOAc 1/1 as the eluent.After evaporation intermediate 25-4 was isolated as a white powder (9.52g, 59%). m/z=248 (M+H)⁺.

Step 5: Synthesis of (3-isopentyl-3H-imidazo[4,5-b]pyridin-2-yl)methanol25-5

Intermediate 25-4 (9.52 g, 38.5 mmol) was dissolved in dry THF (125 mL).The mixture was cooled to 0° C. in an ice-bath. Lithium aluminum hydride(1.46 g, 38.5 mmol) was added portion wise. The resulting mixture wasstirred at 0° C. for 10 minutes and then at room temperature overnight.A solution of saturated NaHCO₃ (10 mL) was added dropwise to thereaction mixture. The resulting mixture was stirred at room temperaturefor 1 h. Then EtOAc (200 mL) was added. The organic layer was thenwashed with water (100 mL) dried over MgSO₄ and evaporated. The residuewas purified by column chromatography using EtOAc/MeOH/NH₃ 9/1 as theeluent. After evaporation intermediate 25-5 was isolated as a whitepowder (0.58 g, 7%). m/z=220 (M+H)⁺.

Step 6: Synthesis of4-chloro-3-((3-isopentyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one25

Compound 25 was prepared in the same manner as compound 10 usingintermediates 25-5 and 14-d as starting material m/z=414 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J=6.4 Hz, 6 H), 1.59 (d,J=7.0 Hz, 6 H), 1.68-1.85 (m, 3 H), 4.37-4.44 (m, 2 H), 4.76 (spt, J=7.1Hz, 1 H), 5.66 (s, 2 H), 7.10 (d, J=5.5 Hz, 1 H), 7.15 (dd, J=8.0, 4.7Hz, 1 H), 7.88 (dd, J=8.0, 1.6 Hz, 1 H), 8.09 (d, J=5.5 Hz, 1 H), 8.34(dd, J=4.8, 1.5 Hz, 1 H)

Synthesis of3-((3-isopentyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-4-carbonitrile29

The mixture of compound 25 (0.075 g, 0.182 mmol),tetrakis(triphenyl-phosphine)palladium (41 mg, 0.036 mmol) anddicyanozinc (0.042 g, 0.363 mmol) in DMF (3 mL) under nitrogenatmosphere was irradiated for 30 minutes in a microwave reactor at 170°C. The resulting mixture was allowed to cool down to room temperaturethen filtered through an acrodisk filter and evaporated to dryness. Theresidue was purified by column chromatography using EtOAc. The titlecompound 29 was isolated as a white solid (60 mg, 81%).

m/z=404 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00 (d, J=6.6 Hz, 6 H), 1.52 (d, J=7.0Hz, 6H), 1.68 (spt, J=6.6 Hz, 1 H), 1.74-1.83 (m, 2 H), 4.38-4.46 (m, 2H), 4.74 (spt, J=7.2 Hz, 1 H), 5.71 (s, 2 H), 7.23 (dd, J=8.0, 4.7 Hz, 1H), 7.81 (d, J=5.3 Hz, 1 H), 7.94 (dd, J=8.0, 1.6 Hz, 1 H), 8.34 (dd,J=4.9, 1.4 Hz, 1 H), 8.37 (d, J=5.3 Hz, 1 H)

EXAMPLE 31 Synthesis of1-cyclopropyl-3-((1-isopentyl-1H-imidazo[4,5-c]pyridin-2-yl)methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one33

Compound 33 was prepared in the same manner as compound 7 using4-chloro-3-nitropyridine (CAS 13091-23-1) and isopentylamine (CAS107-85-7) as starting material. m/z=377 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 (d, J=6.6 Hz, 6 H), 1.00-1.05(m, 2 H), 1.13-1.23 (m, 2 H), 1.44-1.55 (m, 2 H), 1.65-1.78 (m, 1 H),2.86-2.98 (m, 1 H), 4.28-4.36 (m, 2 H), 5.38 (s, 2 H), 7.14 (dd, J=5.4,0.7 Hz, 1 H), 7.25 (d, J=1.2 Hz, 1 H), 8.34 (d, J=5.3 Hz, 1 H), 8.43 (d,J=5.7 Hz, 1 H), 8.64 (s, 1 H), 9.08 (d, J=1.0 Hz, 1 H)

EXAMPLE 32 Synthesis of1-cyclopropyl-3-((1-isopentyl-1H-imidazo[4,5-c]pyridin-2-yl)methyl-1H-benzo[d]imidazol-2(3H)-one31

Compound 31 was prepared in the same manner as compound 33 usingintermediate 13-d as starting material in the last step. m/z=376 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (d, J=6.5 Hz, 6 H), 0.99-1.07(m, 2 H), 1.08-1.20 (m, 2 H), 1.37-1.48 (m, 2 H), 1.68 (dquin, J=13.3,6.7, 6.7, 6.7, 6.7 Hz, 1 H), 2.90 (tdd, J=6.9, 6.9, 3.8, 3.5 Hz, 1 H),4.25-4.41 (m, 2 H), 5.37 (s, 2 H), 7.07-7.15 (m, 2 H), 7.16-7.23 (m, 1H), 7.25 (dd, J=5.8, 1.0 Hz, 1 H), 7.32-7.43 (m, 1 H), 8.41 (d, J=5.8Hz, 1 H), 9.09 (d, J=0.8 Hz, 1 H)

EXAMPLE 33 Synthesis of1-cyclopropyl-5-fluoro-3-((1-isopentyl-1H-imidazo[4,5-c]pyridin-2-yl)methyl-1H-benzo[d]imidazol-2(3H)-one32

Compound 32 was prepared in the same manner as compound 33 usingintermediate 12-d as starting material in the last step. m/z=394 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=6.5 Hz, 6 H), 1.00-1.05(m, 2 H), 1.10-1.17 (m, 2 H), 1.40-1.50 (m, 2 H), 1.70-1.73 (m, 1 H),2.88-3.02 (m, 1 H), 4.29-4.39 (m, 2 H), 5.33 (s, 2 H), 6.74-6.84 (m, 1H), 7.09 (dd, J=8.5, 4.5 Hz, 1 H), 7.19 (dd, J=8.5, 2.3 Hz, 1 H),7.24-7.27 (m, 1 H), 8.42 (d, J=5.5 Hz, 1 H), 9.10 (s, 1 H)

EXAMPLE 34 Synthesis of3-((1-isopentyl-1H-imidazo[4,5-c]pyridin-2-yl)methyl-1-(oxetan-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one36

Compound 36 was prepared in the same manner as compound 33 usingintermediate 11-d as starting material in the last step. m/z=393 (M+H)⁺.

Synthesis of3-((1-(4-benzyloxy)butyl)-4-chloro-1H-imidazo[4,5-c]pyridin-2-yl)methyl-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one38

Step 1: Synthesis of1-(4-benzyloxy)butyl)-4-chloro-2-(diethoxymethyl)-1H-imidazo[4,5-c]pyridine38-2

Intermediate 38-1 was prepared in the same manner as intermediate 10-3in a three step synthesis using 2,4-dichloro-3-nitropyridine (CAS5975-12-2) and 4-aminobutan-1-ol (CAS 13325-10-5) as starting material.

To a solution of intermediate 38-1 (8.05 g, 24.55 mmol) in dry THF (100mL). stirred and cooled at 0° C. were added benzyl bromide (3.06 mL,25.8 mmol), tetrabutyl ammonium iodide (90.7 mg, 0.24 mmol). To theresulting mixture sodium hydride (1.08 g, 27.02 mmol) was addedportionwise. The resulting mixture was stirred at room temperatureovernight. The solvent was removed and the residue was dissolved indichloromethane (200 mL). The resulting mixture was poured in ice/waterand stirred for 10 minutes. The organic layer was separated and theaqueous layer was extracted with dichloromethane (2×100 mL). Thecombined organic layers were dried over Na₂SO₄ and evaporated. Theresidue was purified by column chromatography using EtOAc. The titleintermediate 38-2 was isolated as a yellow oil (8.75 g, 85%). m/z=419(M+H)⁺.

Compound 38 was prepared in the same manner as compound 10 in a 3 stepsynthesis using intermediate 38-2 as starting material. m/z=504 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94-1.02 (m, 2 H), 1.13-1.21 (m, 2H), 1.59-1.76 (m, 4 H), 2.88 (tdd, J=7.0, 7.0, 3.6, 3.5 Hz, 1 H), 3.45(t, J=5.5 Hz, 2 H), 4.35 (t, J=7.4 Hz, 2 H), 4.44 (s, 2 H), 5.40 (s, 2H), 7.01-7.09 (m, 1 H), 7.18 (d, J=5.8 Hz, 1 H), 7.22-7.37 (m, 5 H),8.15 (d, J=5.8 Hz, 1 H), 8.33 (d, J=5.3 Hz, 1 H), 8.68 (d, J=0.5 Hz, 1H)

EXAMPLE 35 Synthesis of1-cyclopropyl-3-((1-(4-hydroxybutyl)-1H-imidazo[4,5-c]pyridin-2-yl)methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one35

To intermediate 38 (0.5 g, 0.99 mmol) in methanol (100 mL), potassiumacetate (0.146 g, 1.5 mmol) and wet 10% Pd/C (0.2 g) were added. Thereaction mixture was stirred at 25° C. under hydrogen atmosphere. Afteruptake of H₂ (1 eq), the catalyst was filtered off and the filtrate wasevaporated. The residue was dissolved in water and dichloromethane. Theresulting mixture was successively extracted with dichloromethane, driedover MgSO₄ and concentrated. The residue was purified by columnchromatography using dichloromethane/methanol. The title compound 35 wascollected as a white powder (125 mg, 31%). m/z=379 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.86-0.99 (m, 2 H), 1.08 (m, J=5.3 Hz, 2 H),1.37-1.54 (m, 2 H), 1.71 (ddd, J=14.6, 7.7, 7.4 Hz, 2 H), 3.01 (tt,J=6.9, 3.2 Hz, 1 H), 3.37-3.48 (m, 2 H), 4.38 (t, J=7.4 Hz, 2 H), 4.48(t, J=5.0 Hz, 1 H), 5.45 (s, 2 H), 7.29 (d, J=5.3 Hz, 1 H), 7.66 (d,J=5.5 Hz, 1 H), 8.26 (d, J=5.3 Hz, 1 H), 8.34 (d, J=5.5 Hz, 1 H), 8.39(s, 1 H), 8.87 (s, 1 H)

EXAMPLE 36 Synthesis of1-cyclopropyl-3-((4-(dimethylamino)-1-(4-hydroxybutyl)-1H-imidazo[4,5-c]pyridin-2-yl)methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one37

Compound 38 (0.5 g, 0.99 mmol) was put in a microwave tube and dimethylamine (2M solution in MeOH, 10 mL) was added. The resulting mixture washeated to 125° C. in a microwave oven for 4 hours. The reaction mixturewas allowed to cool to room temperature then evaporated to dryness. Theresidue (510 mg) containing the intermediate 37-1 was dissolved inmethanol (50 mL) and potassium acetate (0.195 g, 1.99 mmol) and wet 10%Pd/C (0.2 g) were added. The reaction mixture was stirred at 50° C.under hydrogen atmosphere for 48 hours. After uptake of H₂ (1 eq), thecatalyst was filtered off and the filtrate was evaporated. The residuewas dissolved in a mixture of water and dichloromethane. The resultingmixture was successively extracted with dichloromethane, dried overMgSO₄ and concentrated. The residu was purified by column chromatographyusing dichloromethane/methanol. The title compound 37 was collected as awhite powder (140 mg, 32%). m/z=422 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.86-0.93 (m, 2 H), 1.07-1.12 (m, 2 H),1.33-1.44 (m, 2 H), 1.48-1.62 (m, 2 H), 2.97 (tdd, J=7.0, 7.0, 3.6, 3.5Hz, 1 H), 3.33 (s, 6 H), 3.3-3.38 (m, 2 H), 4.22 (t, J=7.5 Hz, 2 H),4.43 (t, J=4.9 Hz, 1 H), 5.34 (s, 2 H), 6.80 (d, J=5.5 Hz, 1 H), 7.26(d, J=5.3 Hz, 1 H), 7.78 (d, J=5.8 Hz, 1 H), 8.23 (d, J=5.3 Hz, 1 H),8.44 (s, 1 H)

EXAMPLE 37 Synthesis of1-cyclopropyl-3-((3-isopentyl-3H-imidazo[4,5-c]pyridin-2-yl)methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one34

Step 1: Synthesis of 3-(isopentylamino)-4-nitropyridine 1-oxide 34-1

3-bromo-4-nitropyridine 1-oxide (CAS 1678-49-5, 10 g, 46 mmol) wasdissolved in ethanol (400 mL). To the resulting mixture3-methylbutan-1-amine (21.8 g, 250 mmol) was slowly added. The reactionmixture was stirred overnight at room temperature and concentrated underreduced pressure. The residue was dissolved in CH₂Cl₂ (500 mL) andwashed with a saturated aqueous solution of NaHCO₃ (500 mL). Thecombined aqueous layers were extracted with CH₂Cl₂ (3×150 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated to givethe intermediate 34-1 (9.8 g, 94%).

Step 2: Synthesis of N³-isopentylpyridine-3,4-diamine 34-2

Intermediate 34-1 (15 g, 66 mmol) in methanol (600 mL) was hydrogenated(1 atm) with Raney Ni (6 g) as a catalyst at 20° C. overnight. Afteruptake of H₂ (4 eq.), the catalyst was removed by filtration. Thefiltrate was concentrated to a pink residue which was washed withtert-butyl methyl ether and CH₃CN to give the intermediate 34-2 (7 g,59%).

Compound 34 was prepared in the same manner as compound 10 in a 4 stepsynthesis using intermediate 34-2 as starting material. m/z=377 (M+H)⁺.

¹H NMR (360 MHz, CHLOROFORM-d) δ ppm 0.9-1.1 (m, 2H), 1.00 (d, J=6.6 Hz,6 H), 1.13-1.23 (m, 2 H), 1.49-1.63 (m, 2 H), 1.66-1.82 (m, 1 H),2.85-3.00 (m, 1 H), 4.33-4.50 (m, 2 H), 5.38 (s, 2 H), 7.15 (d, J=5.5Hz, 1 H), 7.67 (d, J=5.5 Hz, 1 H), 8.34 (d, J=5.1 Hz, 1 H), 8.45 (d,J=5.5 Hz, 1 H), 8.64 (s, 1 H), 8.78 (s, 1 H)

EXAMPLE 38 Synthesis of3-((5-chloro-1-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one39

Step 1: Synthesis of(5-chloro-1-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol39-3

This was prepared in the same manner as the intermediate 1-3 using 1-1and 4,4,4-trifluorobutanal as starting materials.

Step 2:

Compound 39 was prepared in the same manner as compound 1 usingintermediates 39-3 and 10-d as starting materials. m/z=451 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (s, 2 H), 1.12-1.23 (m, 2 H),1.83-1.99 (m, 2 H), 2.12-2.31 (m, 2 H), 2.91 (spt, J=3.50 Hz, 1 H),4.38-4.54 (m, 2 H), 5.38 (s, 2 H), 7.13 (dd, J=5.27, 0.50 Hz, 1 H), 7.27(d, J=8.28 Hz, 1 H), 7.61 (d, J=8.53 Hz, 1 H), 8.36 (d, J=5.27 Hz, 1 H),8.77 (s, 1 H)

EXAMPLE 39 Synthesis of3-((5-chloro-1-(4-fluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one40

Compound 40 was made by a two step fluorination of compound 14.

Compound 14 (5.4 g, 13.1 mmol) and DABCO (4.4 g, 39.2 mmol) were addedto dry CH₂Cl₂ (50 ml) and the resulting solution was stirred at 0° C.under N₂. Tos-Cl (5.0 g, 26.2 mmol) was added portion wise to themixture at 0° C. The mixture was stirred for 2 h at 15° C. The mixturewas washed with 1N HCl (2×20 ml), saturated NaHCO₃ (40 ml) and brine (20ml), dried over NaSO₄ and evaporated to dryness. 7.3 g of product wasobtained as white powder. (Purity 85%, yield 98%). The tosylatedintermediate (7.3 g, 12.9 mmol) was added to CH₃CN (HPLC grade, 70 ml).TBAF (6.7 g, 25.7 mmol, dried by co-evaporation with toluene) was addedto the mixture. The mixture was refluxed for 15 min. The solvent wasremoved under vacuum. Water (200 ml) was added to the mixture and themixture was extracted with CH₂Cl₂ (2*200 ml). The extractions werecombined and concentrated under vacuum. The resulting residue wascombined with 1.1 g of product (Purity 80%) obtained previously and thenpurified by high-performance liquid chromatography (C18, eluent:CH₃CN/H₂O from 15/85 to 35/65 with 0.5% of TFA as buffer). The collectedfractions were combined and neutralized with NaHCO₃. The organic solventwas removed under vacuum. The mixture was filtered and the solid waswashed with H₂O (200 ml). After drying under high vacuum, 3.075 g ofproduct was obtained as white powder. (Purity 98%). m/z=415 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.88-0.96 (m, 2 H) 1.07 (m, J=5.02 Hz, 2 H)1.60-1.85 (m, 4 H) 2.99 (tt, J=6.96, 3.58 Hz, 1 H) 4.45 (m, J=5.65, 5.65Hz, 4 H) 5.46 (s, 2 H) 7.30 (d, J=5.27 Hz, 1 H) 7.36 (d, J=8.28 Hz, 1 H)8.19 (d, J=8.53 Hz, 1 H) 8.27 (d, J=5.27 Hz, 1 H) 8.41 (s, 1 H).

EXAMPLE 40 Synthesis of1-cyclopropyl-3-((1-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one41

Compound 41 was prepared by Pd catalysed reduction of compound 39.

Compound 39 (1000 mg, 2.22 mmol) was dissolved in 30 mL MeOH. Pd/C (10%)and KOAc (218 mg, 2.22 mol) were added. The mixture was placed under H₂and hydrogenated overnight. The mixture was filtrated over a plug ofdicalite and evaporated. Compound 41 was purified by columnchromatography on silicagel using CH₂Cl₂ to CH₂Cl₂/MeOH (NH₃) 9-1 as theeluent. After evaporation 550 mg (59% yield) of 41 was obtained as awhite solid with a purity of 99%. m/z=417 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.93-1.05 (m, 2 H), 1.18 (s, 2 H), 1.91 (s, 2 H),2.12-2.31 (m, 2 H), 2.91 (tt, J=6.93, 3.48 Hz, 1 H), 4.46 (t, J=7.80 Hz,2 H), 5.42 (s, 2 H), 7.14 (d, J=5.27 Hz, 1 H), 7.25 (dd, J=8.28, 4.77Hz, 1 H), 7.66 (dd, J=8.16, 1.38 Hz, 1 H), 8.36 (d, J=5.27 Hz, 1 H),8.59 (dd, J=4.77, 1.51 Hz, 1 H), 8.80 (s, 1 H).

EXAMPLE 41 Synthesis of1-cyclopropyl-3-((1-(4-fluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one42

Compound 42 was prepared in the same manner as compound 11 usingintermediates 42-5 and 10-d as starting materials.

To a suspension of(1-(4-fluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 42-5 (958 mg,4.3 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (950mg, 5.15 mmol) and triphenylphosphine (1350 mg, 5.15 mmol) in 30 ml dryTHF was added (E)-diisopropyl diazene-1,2-dicarboxylate (1.26 ml, 6.43mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 16 hours. The precipitate was filtered off and washedwith some diethyl ether to obtain the title product as a white powder(1036 mg, 63%).

m/z=381 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88-0.96 (m, 2 H)1.04-1.12 (m, 2 H) 1.60-1.86 (m, 4 H) 3.00 (tt, J=6.78, 3.26 Hz, 1 H)4.34-4.56 (m, 4 H) 5.45 (s, 2 H) 7.27 (dd, J=8.16, 4.64 Hz, 1 H) 7.30(d, J=5.27 Hz, 1 H) 8.08 (d, J=7.28 Hz, 1 H) 8.26 (d, J=5.27 Hz, 1 H)8.37 (d, J=4.02 Hz, 1 H) 8.42 (s, 1 H)

Intermediate 42-5 was prepared in the same manner as intermediate 11-5using the TFA salt of 4-fluorobutan-1-amine and 3-fluoro-2-nitropyridineas starting materials.

EXAMPLE 42 Synthesis of1-cyclopropyl-3-((1-(4,4-difluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one43

This compound was prepared in a similar way as compound 11 usingintermediates 43-5 and 10-d as starting materials.

To a suspension of(1-(4,4-difluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 43-5 (470mg, 1.9 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d(431 mg, 2.3 mmol) and triphenylphosphine (613 mg, 2 3 mmol) in 14 mldry THF was added (E)-diisopropyl diazene-1,2-dicarboxylate (0.6 ml, 2.9mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 16 hours. The precipitate was filtered off and washedwith some diethyl ether to obtain the title product as a white powder(450 mg, 58%). m/z=399 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88-0.96 (m, 2 H) 1.04-1.12 (m, 2 H)1.79-1.99 (m, 4 H) 2.99 (tt, J=7.00, 3.54 Hz, 1 H) 4.43 (t, J=7.28 Hz, 2H) 5.46 (s, 2 H) 6.11 (tt, J=57.00, 4.30 Hz, 1 H) 7.24-7.34 (m, 2 H)8.09 (dd, J=8.28, 1.51 Hz, 1 H) 8.27 (d, J=5.27 Hz, 1 H) 8.38 (dd,J=4.77, 1.51 Hz, 1 H) 8.43 (s, 1 H)

Intermediate 43-5 can be prepared in the same manner as intermediate11-5 using 4,4-difluorobutan-1-amine hydrochloride and3-fluoro-2-nitropyridine as starting materials.

4,4-difluorobutan-1-amine hydrochloride 15-e can be prepared as depictedin scheme 15 below.

Step 1: Synthesis of 2-(4,4-diethoxybutylcarbamoyl)benzoic acid 15-a

To a solution of isobenzofuran-1,3-dione (10.5 g, 70.889 mmoles), DMAP(824 mg, 0.1 eq) and triethylamine (10.323 mL, 1.1 eq) in THF (100 mL)was added 4,4-diethoxybutan-1-amine (12.095 g, 1 eq) dropwise viasyringe, over 10 minutes, at 0° C. The reaction mixture was then allowedto warm up to RT and was stirred overnight. Concentration of thereaction mixture in vacuo provided the desired compound 15-a (20.9 g,quantitative yield), which was used without purification in the nextstep. m/z=308 (M−H)⁻

Step 2: Synthesis of 2-(4,4-diethoxybutyl)isoindoline-1,3-dione 15-b

A mixture of 2-(4,4-diethoxybutylcarbamoyl)benzoic acid 15-a (20.8 g,67.235 mmoles) and sodium acetate (2.757 g, 0.5 eq) in acetic anhydride(95 mL) was heated at 110° C. for 3 hours. The reaction mixture was thencooled to RT and poured into 700 mL of ice-water. After stirring for 2hours, it was then extracted with EtOAc. The combined organic layerswere washed with a saturated aqueous NaHCO₃ solution, dried on Na₂SO₄,filtered, and evaporated to dryness to give the desired product 15-b(19.6 g, quantitative yield) which was used as such in the nextreaction.

Step 3: Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butanal 15-c

To a solution of 2-(4,4-diethoxybutyl)isoindoline-1,3-dione 15-b (19.6g, 67.274 mmoles) in THF (130 mL) were added PTSA monohydrate (734 mg,0.05 eq) and water (17 mL, 14 eq). The reaction mixture was stirred for72 h at RT. Water (3 mL) and PTSA monohydrate (150 mg) were then addedand stirring continued overnight. The reaction mixture was then dilutedwith 300 mL EtOAc, washed with NaHCO₃, then brine, dried over sodiumsulfate, filtrated and evaporated to dryness. The crude was purified byflash chromatography using EtOAC as the eluent to provide 14 g (95%yield) of the desired compound 15-c as a brown oil which solidified uponstanding. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03 (quin, J=7.1 Hz,2H), 2.54 (td, J=7.3 Hz, 2H), 3.75 (t, J=6.8 Hz, 2H), 7.70-7.74 (m, 2H),7.79-7.92 (m, 2H), 9.78 (t, J=1.1 Hz, 1H).

Step 4: Synthesis of 2-(4,4-difluorobutyl)isoindoline-1,3-dione 15-d

To a stirred suspension of diethylaminodifluorosulfoniumtetrafluoroborate (3.162 g, 13.81 mmoles) in CH2Cl2 (90 mL) at RT wereadded 4-(1,3-dioxoisoindolin-2-yl)butanal 15-c (2 g, 9.207 mmoles) andtriethylamine trihydrofluoride (2.226 g, 1.5 eq). The mixture wasstirred under N₂ atmosphere overnight. 100 mL of a saturated NaHCO₃solution was added and the mixture was stirred for 10 minutes, until gasevolution stopped. The reaction mixture was then extracted with 150 mLDCM (2×). The combined organic layers were dried on Na₂SO₄, filtratedand evaporated to dryness. The crude was purified by flashchromatography using DCM as the eluent to provide 1.6 g (72% yield) ofthe desired compound 15-d as a yellowish oil. m/z=240 (M+H)⁺; ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.78-1.99 (m, 4H), 3.75 (t, J=6.8 Hz, 2H),5.86 (tt, J=56.5, 3. Hz), 7.68-7.77 (m, 2H), 7.81-7.90 (m, 2H).

Step 5: Synthesis of 4,4-difluorobutan-1-amine 15-e

A solution of 2-(4,4-difluorobutyl)isoindoline-1,3-dione 15-d (8 g,33.442 mmoles) and hydrazine (1.788 mL, 1.1 eq, 1.0 M in water) in 20 mLEtOH was heated at reflux for 2 hours. The mixture was then cooled in anice-bath. The resulting precipitate of 2,3-dihydrophthalazine-1,4-dionewas filtered off and the filtrate was concentrated in vacuo to give thedesired compound 15-e (3.6 g) which was used as such in the nextreaction.

EXAMPLE 43 Synthesis of1-cyclopropyl-3-((1-isopentyl-5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one44

This compound was prepared in a similar way as compound 11 usingintermediates 44-3 and 10-d as starting materials.

To a suspension of(1-isopentyl-5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol44-3 (1.0 g, 3.5 mmol (73% purity)),1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (731.8 mg, 4.2mmol) and triphenylphosphine (1.1 g, 4.2 mmol) in 24 ml dry THF wasadded (E)-diisopropyl diazene-1,2-dicarboxylate (1.0 ml, 5.2 mmol) atroom temperature. The reaction mixture was stirred at room temperaturefor 16 hours. The reaction mixture was evaporated to dryness andpurified by preparative column chromatography to obtain 44 as a whitesolid (578.0 mg, 37%). m/z=445 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.02 (m, J=6.50 Hz, 8H) 1.13-1.24 (m, 2 H) 1.48-1.64 (m, 2 H) 1.73(dquin, J=13.19, 6.49, 6.49, 6.49, 6.49 Hz, 1 H) 2.92 (tt, J=6.81, 3.48Hz, 1 H) 4.35-4.52 (m, 2 H) 5.41 (s, 2 H) 7.13 (d, J=5.27 Hz, 1 H) 7.61(d, J=8.28 Hz, 1 H) 7.79 (d, J=8.28 Hz, 1 H) 8.34 (d, J=5.27 Hz, 1 H)8.68 (s, 1 H).

Intermediate 44-3 was prepared in the same manner as intermediate 39-3using 44-1 and 3-methylbutanal as the starting materials.

EXAMPLE 45

EXAMPLE 47 Synthesis of3-{[5-chloro-1-(4-hydroxypentyl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one(67) Step 1: synthesis of4-(5-chloro-2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-imidazo[4,5-b]pyridin-1-yl)butanal(67-1)

To the alcohol 14 (5 g, 12.11 mmoles) dissolved in DCM (80 mL) was addeddess-martin periodinane (6.934 g, 1.35 eq, CAS 87413-09-0). Theresulting mixture was stirred at Rt overnight. Diethylether was added(150 mL) and the mixture was stirred for 15 minutes. The mixture wasfiltrated and the filtrate washed quickly with an aqueous Na₂S₂O₃solution, dried on Na₂SO₄, filtrated and evaporated. The resulting solidwas washed again with a solution of 5% methanol in dichloromethane andthe filtrate was washed with a Na₂S₂O₃ solution and dried over Na₂SO₄.The solution was concentrated and the aldehyde 67-1 was obtained as alight yellow solid (4.6 g, 93% yield) and was used as such in the nextstep. LCMS m/z=411 (M+H)⁺

Step 2: Synthesis of3-{[5-chloro-1-(4-hydroxypentyl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one(67)

In a 100 mL dry flask,4-{5-chloro-2-[1-cyclopropyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)methyl]-1H-imidazo[4,5-b]pyridin-1-yl}butanal67-1 (1.5 g, 3.6 mmol) was dissolved in dry THF (50 mL) and cooled until−20° C. under N₂ atmosphere. An excess methylmagnesium iodide (3M inTHF) (1.8 mL, 5.5 mmol, 1.5 eq.) was then gently added dropwise to thecooled solution via syringe. The solution was warmed up until ambienttemperature and stirred for 4 hours. The solution was diluted with 30 mLNaHCO₃ solution and extracted with EtOAC (30 mL). The combined organicswere dried (MgSO₄) and concentrated in vacuo. The crude was purified onRP SunFire Prep column (C18 OBD-10 μm,30×150 mm), using a 0.25% NH₄HCO₃solution in water-MeOH solution to give 350 mg (22%) of3-{[5-chloro-1-(4-hydroxypentyl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-1-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one(67) as a white solid.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.05 (m,2 H) 1.13-1.22 (m, 5 H) 1.43-1.57 (m, 2H) 1.77-1.91 (m, 2 H) 2.11 (br.s, 1 H) 2.89-2.98 (m, 1 H) 3.81-3.90 (m, 1 H) 4.32-4.50 (m, 2 H) 5.40(s, 2 H) 7.13 (dd, J=5.27, 0.75 Hz, 1 H) 7.23 (d, J=8.53 Hz, 1 H) 7.65(d, J=8.28 Hz, 1 H) 8.34 (d, J=5.27 Hz, 1 H) 8.75 (s, 1 H); LCMS m/z=427(M+H)⁺

EXAMPLE 48 Synthesis of3-((5-chloro-1-(4-hydroxy-4-methylpentyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (75) Step 1: Synthesis of3-((5-chloro-1-(4-oxopentyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one(75-1)

To the alcohol 67 (380 mg, 0.89 mmoles) dissolved in DCM (30 mL) wasadded dess-martin periodinane (509 mg, 1.35 eq, CAS 87413-09-0). Theresulting mixture was stirred at Rt overnight. Diethylether was added(150 mL) and the mixture was stirred for 15 minutes. The mixture wasfiltrated and the filtrate washed quickly with an aqueous Na₂S₂O₃solution, dried on Na₂SO₄, filtrated and evaporated. The resulting solidwas purified by flash chromatography (10% MeOH in DCM) and the aldehyde75 was obtained as a light yellow solid (218 mg, 58% yield). LCMSm/z=425 (M+H)⁺

Step 2: Synthesis of3-((5-chloro-1-(4-hydroxy-4-methylpentyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (75)

To a solution of ketone 75-1 (210 mg, 0.497 mmole) in THF was added MeLi(0.466 mL, 1.5 eq, 1.6 M in THF) dropwise, at 0° C. The resultingmixture was stirred at RT overnight, then was heated at 50° C. for 2hours. After cooling to RT, the reaction mixture was poured in water,extracted with dichloromethane, dried over MgSO₄ and concentrated. Theresidue was purified by column chromatography using dichloromethane andmethanol, followed by a purification by prep HPLC on RP SunFire Prep C18OBD-10 μm,30×150 mm, and mobile phase (0.25% NH4HCO3 solution in water,CH3CN) to give 11 mg of the desired compound 75. LCMS m/z=441 (M+H)⁺; ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 0.97-1.05 (m, 2 H), 1.11-1.22 (m, 2H), 1.17 (s, 6 H), 1.43-1.53 (m, 2 H), 1.74 (br. s., 1 H), 1.79-1.91 (m,2 H), 2.82-3.05 (m, 1 H), 4.40 (t, J=7.5 Hz, 2 H), 5.39 (s, 2 H), 7.11(d, J=5.0 Hz, 1 H), 7.20 (d, J=8.3 Hz, 1 H), 7.64 (d, J=8.3 Hz, 1 H),8.31 (d, J=5.0 Hz, 1 H), 8.70 (s, 1 H).

EXAMPLE 49

Characterization of compounds, and test for RSV inhibitory activity areshown in tables 1-5.

General Experimental Details

HPLC-MS analysis was done using either one of the following methods:

Method 1:

The HPLC measurement was performed using an Agilent 1100 modulecomprising a pump, a diode-array detector (DAD) (wavelength used 220nm), a column heater and a column as specified below. Flow from thecolumn was split to an Agilent MSD Series G1946C and G1956A. MS detectorwas configured with API-ES (atmospheric pressure electrosprayionization). Mass spectra were acquired by scanning from 100 to 1000.The capillary needle voltage was 2500 V for positive ionization mode and3000 V for negative ionization mode. Fragmentation voltage was 50 V.Drying gas temperature was maintained at 350° C. at a flow of 10 l/min.Reversed phase HPLC was carried out on a YMC-Pack ODS-AQ, 50×2.0 mm 5 mmcolumn with a flow rate of 0.8 ml/min. Two mobile phases (mobile phaseA: water with 0.1% TFA; mobile phase B: acetonitrile with 0.05% TFA)were used. First, 100% A was hold for 1 minute. Then a gradient wasapplied to 40% A and 60% B in 4 minutes and hold for 2.5 minutes.Typical injection volumes of 2 mL were used. Oven temperature was 50° C.(MS polarity: positive)

Method 2:

The HPLC measurement was performed using an Agilent 1100 modulecomprising a pump, a diode-array detector (DAD) (wavelength used 220nm), a column heater and a column as specified below. Flow from thecolumn was split to a Agilent MSD Series G1946C and G1956A. MS detectorwas configured with API-ES (atmospheric pressure electrosprayionization). Mass spectra were acquired by scanning from 100 to 1000.The capillary needle voltage was 2500 V for positive ionization mode and3000 V for negative ionization mode. Fragmentation voltage was 50 V.Drying gas temperature was maintained at 350° C. at a flow of 10 l/min.Reversed phase HPLC was carried out on a YMC-Pack ODS-AQ, 50×2.0 mm 5 mmcolumn with a flow rate of 0.8 mL/min. Two mobile phases (mobile phaseA: water with 0.1% TFA; mobile phase B: acetonitrile with 0.05% TFA)were used. First, 90% A and 10% B was hold for 0.8 minutes. Then agradient was applied to 20% A and 80% B in 3.7 minutes and hold for 3minutes. Typical injection volumes of 2 mL were used. Oven temperaturewas 50° C. (MS polarity: positive)

Method 3:

Column: XTerra MS C18 2.5μ, 4.6×50 mm, mobile phase A: 10 mMNH₄OOCH+0.1% HCOOH in H₂O, mobile phase B: MeOH operating at a columntemperature of 50° C. using a flow rate of 1.5 mL/min. Gradientconditions: t=0 min: 65% A, 35% B; t=3.5 min, 5% A, 95% B; t=5.5 min, 5%A, 95% B; t=5.6 min: 65% A, 35% B; t=7 min, 65% A, 35% B.

Method 4:

Column: SunFire C18 3.5μ. 4.6×100 mm, mobile phase A: 10 mM NH₄OOCH+0.1%HCOOH in H₂O, mobile phase B: MeOH operating at a column temperature of50° C. using a flow rate of 1.5 mL/min. Gradient conditions: t=0 min:65% A, 35% B; t=7 min, 5% A, 95% B; t=9.6 min, 5% A, 95% B; t=9.8 min:65% A, 35% B; t=12 min, 65% A, 35% B.

NMR spectra were recorded on a Bruker Avance 400 spectrometer, operatingat 400 MHz for ¹H. Chemical shifts are given in ppm and a J value in Hz.Multiplicity is indicated using the following abbreviations: d fordoublet, t for a triplet, m for a multiplet, etc. Thin-layerchromatography (TLC) was performed on 5×10 cm aluminium sheets coatedwith Silicagel 60 F₂₅₄ (Merck KGaA).

Antiviral Activity

Black 96-well clear-bottom microtiter plates (Corning, Amsterdam, TheNetherlands) were filled in duplicate using a customized robot systemwith serial 4-fold dilutions of compound in a final volume of 50 μlculture medium [RPMI medium without phenol red, 10% FBS, 0.04%gentamycin (50 mg/mL) and 0.5% DMSO]. Then, 100 μl of a HeLa cellsuspension (5×10⁴ cells/mL) in culture medium was added to each wellfollowed by the addition of 50 μl rgRSV224 (MOI=0.02) virus in culturemedium using a multidrop dispenser (Thermo Scientific, Erembodegem,Belgium). rgRSV224 virus is an engineered virus that includes anadditional GFP gene (Hallak et al, 2000) and was in-licensed from theNIH (Bethesda, Md., USA). Medium, virus- and mock-infected controls wereincluded in each test. Cells were incubated at 37° C. in a 5% CO₂atmosphere. Three days post-virus exposure, viral replication wasquantified by measuring GFP expression in the cells by a MSM lasermicroscope (Tibotec, Beerse, Belgium). The EC₅₀ was defined as the 50%inhibitory concentration for GFP expression. In parallel, compounds wereincubated for three days in a set of white 96-well microtitier plates(Corning) and the cytotoxicity of compounds in HeLa cells was determinedby measuring the ATP content of the cells using the ATPlite kit(PerkinElmer, Zaventem, Belgium) according to the manufacturer'sinstructions. The CC₅₀ was defined as the 50% concentration forcytotoxicity.

REFERENCES

Hallak L K, Spillmann D, Collins P L, Peeples M E. Glycosaminoglycansulfation requirements for respiratory syncytial virus infection. J.Virol. 740, 10508-10513 (2000).

TABLE 1

RSV- TOX- RSV- wt_EC₅₀ TOX- HELA_EC₅₀ N^(o) Name C₅—R₁ C₆—R₁ R₂ R₃ Y—R₄wt_n_EC₅₀ (μM) HELA_n_EC₅₀ (μM)  1 3-((5-chloro-1- isopentyl-1H- imidazo[4,5-b]pyridin-2-yl) methyl)-1- cyclopropyl-1H- imidazo[4,5-c]pyridin-2(3H)-one C—Cl C—H

N 1 0.000365  1 >9.83603   2 3-((5-chloro-1- isopentyl-1H- imidazo[4,5-b]pyridin-2-yl) methyl)-1- (oxetan-3-yl)-1H- imidazo[4,5-c]pyridin-2(3H)-one C—Cl C—H

N 1 0.001583  1 >9.83603   3 4-(5-chloro-2-((1- cyclopropyl-2-oxo-1H-imidazo[4,5-c] pyridin-3(2H)- yl)methyl)-1H- imidazo[4,5-b]pyridin-1yl) butyl pivalate C—Cl C—H

N 1 0.003293  1 >9.83603   4 1-cyclopropyl-3- ((1-isopentyl- 1H-imidazo[4,5-b]pyridin-2-yl) methyl)-1H- benzo[d] imidazol-2(3H)- one C—H C—H

C—H 1 0.007081  1 >9.83603   5 1-cyclopropyl-3- ((1-isopentyl-1H-imidazo [4,5-b]pyridin-2- yl)methyl)- 1H-imidazo [4,5-c]pyridin-2(3H)-one C—H C—H

N 4 0.008665  4 >98.3603    6 3-((5-chloro-1- isopentyl-1H-imidazo[4,5-b] pyridin-2-yl) methyl)-1- cyclopropyl- 5-fluoro-1H-benzo[d]imidazol- 2(3H)-one C—Cl C—H

C—F 2 0.008667  2 >9.83603   7 1-cyclopropyl-3- ((1-(3- (methylsulfonyl)propyl)-1H- imidazo[4,5-b] pyridin-2- yl)methyl)-1H- imidazo[4,5-c]pyridin- 2(3H)-one C—H C—H

N 1 0.013701  2 >9.83603   8 1-cyclopropyl-5- fluoro-3-((1-isopentyl-1H- imidazo[4,5-b] pyridin-2- yl)methyl)-1H- benzo[d]imidazol- 2(3H)-one C—H C—H

C—F 3 0.01586   2 >9.83603   9 3-((1-isopentyl- 1H-imidazo [4,5-b]pyridin-2- yl)methyl)-1- (oxetan-3-yl)- 1H-imidazo[4,5-c]pyridin-2(3H)-one C—H C—H

N 2 0.058072  1 >9.83603  10 1-cyclopropyl-3- ((1-(3- (methoxypropyl)-1H- imidazo[4,5-b] pyridin-2- yl)methyl)-1H- imidazo[4,5- c]pyridin-2(3H)-one C—H C—H

N 2 0.089347  2   4.7555418 11 1-cyclopropyl-3- ((1-(3- (fluoropropyl)-1H-imidazo[4,5-b] pyridin-2- yl)methyl)-1H- imidazo[4,5- c]pyridin-2(3H)-one C—H C—H

N 2 0.090853  2 >9.83603  12 3-((1-(3- methoxypropyl)- 1H- imidazo[4,5-b]pyridin- 2-yl)methyl)-1- (oxetan-3-yl)-1H- imidazo[4,5-c]pyridin- 2(3H)-one C—H C—H

N 1 1.936065  3 >98.3603   13 3-((5-chloro-1- isopentyl-1H-imidazo[4,5-b] pyridin-2-yl) methyl)-3- cyclopropyl- 1H-benzo[d]imidazol- 2(3H)-one C—Cl C—H

C—H 1 0.0023   2 >9.84    14 3-((5-chloro- 1-(4- hydroxybutyl)-1H-imidazo[4,5-b] pyridin-2- yl)methyl)-1- cyclopropyl- 1H-imidazo[4,5-c]pyridin- 2(3H)-one C—Cl C—H

N 1 0.006    2 >9.84    15 1-cyclopropyl-5- fluoro-3-((1-(3-methoxypropyl)- 1H-imidazo [4,5-b] pyridin-2- yl)methyl)-1H- benzo[d]imidazol- 2(3H)-one C—H C—H

C—F 1 0.22    2 >98.3603   39 3-((5-chloro-1- (4,4,4- trifluorobutyl)-1H-imidazo [4,5-b] pyridin-2-yl) methyl)-1- cyclopropyl- 1H-imidazo[4,5-b] pyridin- 2(3H)-one C—Cl C—H

N 3 0.00096   3 >98.3603   40 3-((5-chloro-1-(4- fluorobutyl)-1H-imidazo[4,5-b] pyridin-2-yl) methyl)-1- cyclopropyl-1H- imidazo[4,5-b]pyridin- 2(3H)-one C—Cl C—H

N 9 0.002   11 >98.3603   41 1-cyclopropyl-3- ((1-(4,4,4-trifluorobutyl)- 1H-imidazo[4,5- b]pyridin-2- yl)methyl)-1H-imidazo[4,5- c]pyridin- 2(3H)-one C—H C—H

N 4 0.0071   4 >98.3603   42 1-cyclopropyl-3- ((1-(4- fluorobutyl)-1H-imidazo[4,5-b] pyridin-2-yl) methyl)-1H- imidazo[4,5- c]pyridin-2(3H)-one C—H C—H

N 1 0.0052   1 >98.3603   43 1-cyclopropyl-3- ((1-(4,4- difluorobutyl)-1H- imidazo[4,5-b] pyridin-2- yl)methyl)-1H- imidazo[4,5- c]pyridin-2(3H)-one C—H C—H

N 44 1-cyclopropyl-3- ((1-isopentyl-5- (trifluoromethyl)- 1H-imidazo[4,5-b] pyridin-2-yl) methyl)-1H- imidazo[4,5- c]pyridin-2(3H)-one C—CF₃ C—H

N 1 0.019    1 >98.3603  

TABLE 2

RSV- RSV- TOX- TOX- wt_n_(—) wt_EC₅₀ HELA_n_(—) HELA_EC₅₀ N° Name C₅—R₁C₆—R₁ R₂ R₃ R₄ Y EC₅₀ (μM) EC₅₀ (μM) 16 3-((6-bromo-3-isopentyl-3H-imidazo[4,5-b]pyridin-2- yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)- one C—Br C—H

H N  2 0.008806 4 >98.3603  17 3-((6-(aminomethyl)-3-isopentyl-3H-imidazo[4,5- b]pyridine-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5- c]pyridin-2(3H)-one C—CH₂NH₂ C—H

H N 12 0.011817 3 >98.3603  18 3-((6-bromo-3-isopentyl-3H-imidazo[4,5-b]pyridin-2- yl)methyl)-1-(oxetan-3-yl)-1H-imidazo[4,5-c]pyridin- 2(3H)-one C—Br C—H

H N  3 0.017331 2  >9.83603 19 3-((6-bromo-3-(4- hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2- yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)- one C—Br C—H

H N  3 0.019057 1 >98.3603  20 3-((6-bromo-3-(4- hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2- yl)methyl)-1-(oxetan-3-yl)-1H-imidazo[4,5-c]pyridin- 2(3H)-one C—Br C—H

H N  2 0.036127 3  >9.83603 21 3-((6-chloro-3-(4- hydroxybutyl)-3H-imidazo[4,5-b]pyridin-2- yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)- one C—Cl C—H

H N  2 0.054553 2  >9.83603 22 1-cyclopropyl-3-((6-fluoro-3-(4-hydroxybutyl)-3H- imidazo[4,5-b]pyridin-2- yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one C—F C—H

H N  2 0.402689 2  >9.83603 23 2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)- yl)methyl)-3-isopentyl-3H-imidazo[4,5-b]pyridin-6- ylboronic acid C—B(OH)₂ C—H

H N  3 0.645431 3 >98.3603  24 1-cyclopropyl-3-((3-isopentyl-3H-imidazo[4,5- b]pyridin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)- one C—H C—H

H N  2 1.223404 3 >98.3603  25 4-chloro-3-((3-isopentyl-3H-imidazo[4,5-b]pyridin-2- yl)methyl)-1-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)- one C—H C—H

Cl N  1 8.270276 1 >24.5901  26 methyl 2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5- c]pyridin-3(2H)-yl)methyl)-3-isopentyl-3H-imidazo[4,5- b]pyridine-6-carboxylate C—CO₂Me C—H

H N  1 8.60855 2 >98.3603  27 2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)- yl)methyl)-3-isopentyl-3H-imidazo[4,5-6]pyridine-6- carbonitrile C—CN C—H

H N  1 34.06748 1 >98.3603  28 2-((1-cyclopropyl-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)- yl)methyl)-3-isopentyl-3H-imidazo[4,5-b]pyridine-6- carboxylic acid C—CO₂H C—H

H N  2 >49.1802 2 >49.1802  29 3-((3-isopentyl-3H-imidazo[4,5-b]pyridin-2- yl)methyl)-1-isopropyl-2- oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-4- carbonitrile C—H C—H

CN N  1 >98.3603 1 >98.3603  30 1-((6-bromo-3-isopentyl-3H-imidazo[4,5-b]pyridin-2- yl)methyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one C—Br C—H

H CH 1  >9.84  

TABLE 3

RSV- RSV- TOX- TOX- wt_n_(—) wt_EC₅₀ HELA_n_(—) HELA_EC₅₀ N° Name X₄—R₁X₅—R₁ X₆—R₁ R₂ R₃ Y—R₄ EC₅₀ (μM) EC₅₀ (μM) 31 1-cyclopropyl-3-((1-isopentyl-1H- imidazo[4,5-c]pyridin- 2-yl)methyl-1H- benzo[d]imidazol-2(3H)-one C—H N C—H

C—H  1 0.005399 2  >9.83603 32 1-cyclopropyl-5-fluoro-3-((1-isopentyl-1H- imidazo[4,5- c]pyridin-2-yl)methyl-1H-benzo[d]imidazol- 2(3H)-one C—H N C—H

C—F  2 0.011281 3  >9.83603 33 1-cyclopropyl-3-((1- isopentyl-1H-imidazo[4,5-c]pyridin- 2-yl)methyl-1H- imidazo[4,5- c]pyridin-2(3H)-oneC—H N C—H

N 13 0.030399 2 >98.3603  34 1-cyclopropyl-3- ((3-isopentyl-3H-imidazo[4,5- c]pyridin-2- yl)methyl-1H- imidazo[4,5-c]pyridin-2(3H)-one C—H C—H N

N  2 0.073986 4 >98.3603  35 1-cyclopropyl-3- ((1-(4-hydroxybutyl)-1H-imidazo[4,5- c]pyridin-2- yl)methyl-1H- imidazo[4,5-c]pyridin-2(3H)-one C—H N C—H

N  1 0.079508 1 >98.3603  36 3-((1-isopentyl-1H- imidazo[4,5-c]pyridin-2- yl)methyl-1-(oxetan- 3-yl)-1H- imidazo[4,5-c]pyridin-2(3H)- one C—H N C—H

N  1 0.09487  2  >9.83603 37 1-cyclopropyl-3-((4- (dimethylamino)-1-(4-hydroxybutyl)- 1H-imidazo[4,5- c]pyridin-2- yl)methyl-1H-imidazo[4,5- c]pyridin-2(3H)-one C—NMe₂ N C—H

N  3 0.273628 3  >9.83603 38 3-((1-(4- benzyloxy)butyl)-4-chloro-1H-imidazo[4,5- c]pyridin-2-yl)methyl- 1-cyclopropyl-1H-imidazo[4,5- c]pyridin-2(3H)-one C—Cl N C—H

N  1 1.479585 1 >98.3603 

TABLE 4

WT activity SI EC₅₀ CC₅₀/ X₄—R₁ X5—R₁ R₂ R₃ Y—R₄ ¹H NMR (μM) EC₅₀  99 NC—Cl

N ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96-1.05 (m, 2 H) 1.11-1.26 (m,2 H) 2.06-2.22 (m, 2 H) 2.51 (t, J = 6.90 Hz, 2 H) 2.88-2.97 (m, 1 H)4.57 (t, J = 7.50 Hz, 2 H) 0.010092 >9746 5.38 (s, 2 H) 7.15 (dd, J =5.27, 0.75 Hz, 1 H) 7.29 (d, J = 8.53 Hz, 1 H) 7.72 (d, J = 8.53 Hz, 1H) 8.38 (d, J = 5.27 Hz, 1 H) 8.79 (s, 1 H) 100 N C—Cl

C—H ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.06 (m, 2 H) 1.11-1.20(m, 2 H) 2.01-2.11 (m, 2 H) 2.50 (t, J = 7.03 Hz, 2 H) 2.88-2.95 (m, 1H) 4.57 (t, J = 7.50 Hz, 2 H) 0.020842 >2399 5.37 (s, 2 H) 7.07-7.15 (m,2 H) 7.19-7.23 (m, 1 H) 7.27-7.30 (m, 1 H) 7.57- 7.62 (m, 1 H) 7.70 (d,J = 8.28 Hz, 1 H) 101 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 1.37-1.52 (m, 2 H), 1.66-1.82 (m, 2H), 3.40 (t, J = 6.02 Hz, 2 H), 4.45 (br. s., 1 H), 4.41 (t, J = 7.53Hz, 2 H), 4.92-5.01 (m, 2 H), 5.08 (t, J = 6.65 Hz, 2 H), 5.51 (s, 2 H),5.53-5.62 (m, 1 H), 7.36 0.026525 >3769 (d, J = 8.28 Hz, 1 H), 7.49-7.62 (m, 1 H), 8.17 (d, J = 8.53 Hz, 1 H), 8.32 (d, J = 5.27 Hz, 1 H),8.49 (s, 1 H) 102 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.88-0.95 (m, 2 H) 1.03-1.08 (m, 2 H)2.19 (m, J = 7.65, 7.65, 7.65, 7.65 Hz, 2 H) 2.95-3.04 (m, 4 H) 3.23 (t,J = 8.30 Hz, 2 H) 4.53 (t, J = 7.40 Hz, 2 H) 5.48 (s, 2 H) 7.30 (d, J =5.27 Hz, 1 H) 7.39 (d, J = 8.28 Hz, 1 H) 8.20 (d, J = 8.53 Hz, 1 H)0.00427  >23420 8.27 (d, J = 5.27 Hz, 1 H) 8.43 (s, 1 H) 103 N C—Cl

C—F ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90 (m, J = 2.51 Hz, 2 H)1.00-1.10 (m, 2 H) 2.18 (m, J = 14.62, 7.37, 7.37 Hz, 2 H) 2.94 (tt, J =6.80, 3.40 Hz, 1 H) 2.99 (s, 3 H) 3.22 (t, J = 7.50 Hz, 2 H) 4.52 (t, J= 7.15 Hz, 2 H) 5.41 (s, 2 H) 6.86-7.01 (m, 1 H) 0.003746 >266987.15-7.28 (m, 2 H) 7.39 (d, J = 8.28 Hz, 1 H) 8.19 (d, J = 8.53 Hz, 1 H) 45 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 1.58-1.90 (m, 4 H) 4.36-4.56 (m, 4 H)4.97 (t, J = 7.50 Hz, 2 H) 5.08 (t, J = 6.53 Hz, 2 H) 5.52 (s, 2 H) 5.57(m, J = 6.27, 6.27 Hz, 1 H) 7.37 (d, J = 8.53 Hz, 1 H) 7.550.008491 >11777 (d, J = 5.27 Hz, 1 H) 8.20 (d, J = 8.53 Hz, 1 H) 8.32(d, J = 5.52 Hz, 1 H) 8.50 (s, 1 H)  46 N C—Cl

C—F ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.85-0.95 (m, 2 H) 1.04 (m, J =5.77 Hz, 2 H) 1.65-1.98 (m, 4 H) 2.87-3.04 (m, 4 H) 3.18 (t, J = 7.40Hz, 2 H) 4.43 (t, J = 6.78 Hz, 2 H) 5.40 (s, 2 H) 6.93 (m, J = 18.20,1.88 Hz, 1 H) 7.17 (dd, J = 9.16, 1.88 Hz, 1 H) 7.23 (dd, J = 8.53, 4.52Hz, 0.011567 >8645 1 H) 7.37 (d, J = 8.53 Hz, 1 H) 8.20 (d, J = 8.53 Hz,1 H)  47 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.92 (m, J = 2.51 Hz, 2 H) 1.03-1.12(m, 2 H) 1.68-1.95 (m, 4 H) 2.95 (s, 3 H) 3.01 (tt, J = 6.87, 3.67 Hz, 1H) 3.19 (t, J = 7.30 Hz, 2 H) 4.44 (t, J = 7.15 Hz, 2 H) 5.47 (s, 2 H)7.30 (d, J = 5.02 Hz, 1 H) 7.37 (d, J = 8.53 Hz, 1 H) 8.21 (d, J = 8.53Hz, 1 0.01063  >9407 H) 8.27 (d, J = 5.02 Hz, 1 H) 8.41 (s, 1 H)  48 NC—Cl

C—H ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.96 (m, 2 H) 1.02-1.11 (m, 2H) 1.65- 1.89 (m, 4 H) 2.89-3.01 (m, 4 H) 3.12-3.22 (m, 2 H) 4.43 (t, J= 6.90 Hz, 2 H) 5.40 (s, 2 H) 6.97-7.15 (m, 2 H) 7.21 (d, J = 7.53 Hz, 1H) 7.26 (d, J = 7.53 Hz, 1 H) 7.36 (d, J = 0.003443 >29042 8.28 Hz, 1 H)8.19 (d, J = 8.53 Hz, 1 H)  50 N C—H

H N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 1.38-1.51 (m, 2 H) 1.65-1.77 (m, 2H) 3.41 (t, J = 6.40 Hz, 2 H) 4.38 (t, J = 7.53 Hz, 2 H) 5.44 (s, 2 H)7.08 (dd, J = 5.27, 0.75 Hz, 1 H) 7.26 (dd, J = 8.16, 4.64 Hz, 1 H)0.044745 >2234 8.05 (dd, J = 8.16, 1.63 Hz, 1 H) 8.17 (d, J = 5.27 Hz, 1H) 8.35 (d, J = 0.50 Hz, 1 H) 8.37 (dd, J = 4.77, 1.51 Hz, 1 H)  51 NC—H

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.97 (m, 2 H) 1.09 (m, J = 7.00,7.00 Hz, 2 H) 1.35-1.52 (m, 2 H) 1.64-1.76 (m, 2 H) 3.00 (tt, J = 6.90,3.51 Hz, 1 H) 3.16-3.36 (m, 2 H) 4.38 (t, J = 7.40 Hz, 2 H) 5.45 (s, 2H) 7.21- 0.009607 >10408 7.34 (m, 2 H) 8.05 (dd, J = 8.03, 1.25 Hz, 1 H)8.26 (d, J = 5.27 Hz, 1 H) 8.37 (dd, J = 4.52, 1.25 Hz, 1 H) 8.41 (s, 1H)  54 N C—Cl

C—H ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.98-1.05 (m, 2 H), 1.10-1.17(m, 2 H), 2.18- 2.29 (m, 2 H), 2.88-2.95 (m, 1 H), 2.92 (s, 3 H), 3.12(t, J = 7.3 Hz, 2 H), 4.58-4.65 (m, 2 H), 5.35 (s, 2 H), 7.09- 7.15 (m,2 H), 7.17-7.22 (m, 1 H), 7.24 (d, J = 8.3 Hz, 0.00285 >35091 1 H),7.52-7.57 (m, 1 H), 7.74 (d, J = 8.5 Hz, 1 H)  55 N C—Cl

C—COOEt ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.06 (m, 2 H),1.12-1.20 (m, 2 H), 1.41 (t, J = 7.0 Hz, 3 H), 1.68-1.76 (m, 1 H),1.77-1.89 (m, 3 H), 2.88- 2.96 (m, 1 H), 4.37-4.45 0.027295 >3663 (m, 3H), 4.45-4.5 (m, 2 H), 4.53 (t, J = 5.3 Hz, 1 H), 5.38 (s, 2 H),7.23-7.34 (m, 2 H), 7.62 (d, J = 8.3 Hz, 1 H), 7.88 (dd, J = 8.3, 1.5Hz, 1 H), 8.06 (d, J = 1.3 Hz, 1 H)  56 N C—Cl

C—COOEt ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 (t, J = 7.4 Hz, 3 H),1.41 (t, J = 7.2 Hz, 3 H), 1.69-1.89 (m, 6 H), 3.88 (t, J = 7.3 Hz, 2H), 4.33-4.47 (m, 5 H), 4.52 (t, J = 5.3 Hz, 1 H), 0.036033 >2775 5.42(s, 2 H), 7.01 (d, J = 8.3 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 7.62 (d,J = 8.3 Hz, 1 H), 7.87 (dd, J = 8.3, 1.5 Hz, 1 H), 8.09 (d, J = 1.5 Hz,1 H)  57 N C—Cl

C—COOH ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.97 (m, 2 H), 1.05-1.14(m, 2 H), 1.59- 1.87 (m, 4 H), 3.00-3.05 (m, 1 H), 4.37-4.47 (m, 3 H),4.51 (t, J = 5.5 Hz, 1 H), 5.48 (s, 2 H), 7.35 (dd, J = 8.4, 4.9 Hz, 2H), 7.78 (dd, J = 8.3, 1.5 0.018249 >5479 Hz, 1 H), 7.82 (d, J = 1.3 Hz,1 H), 8.18 (d, J = 8.5 Hz, 1 H), 12.80 (br. s, 1 H)  58 N C—Cl

C—F ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.86-0.94 (m, 2 H), 1.02-1.09 (m, 2H), 1.37-1.50 (m, 2 H), 1.65-1.77 (m, 2 H), 2.90-2.99 (m, 1 H),3.36-3.43 (m, 2 H), 4.35-4.43 (m, 2 H), 4.47 (t, J = 5.0 Hz, 1 H), 5.39(s, 2 H), 6.89-6.97 (m, 1 H), 0.003967 >25206 7.16 (dd, J = 9.0, 2.5 Hz,1 H), 7.22 (dd, J = 8.7, 4.6 Hz, 1 H), 7.35 (d, J = 8.5 Hz, 1 H), 8.16(d, J = 8.3 Hz, 1 H)  43 N C—H

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.88-0.96 (m, 2 H) 1.04-1.13 (m, 2 H)1.73- 2.01 (m, 4 H) 2.99 (tt, J = 6.96, 3.58 Hz, 1 H) 4.43 (t, J = 7.15Hz, 2 H) 5.46 (s, 2 H) 5.93-6.28 (m, 1 H) 7.23-7.36 (m, 0.00791  7161 2H) 8.09 (dd, J = 8.16, 1.38 Hz, 1 H) 8.27 (d, J = 5.27 Hz, 1 H) 8.38(dd, J = 4.64, 1.38 Hz, 1 H) 8.43 (s, 1 H)  64 N C—Cl

N ¹H NMR (360 MHz, DMSO- d₆) δ ppm 0.88-0.98 (m, 2 H), 1.01-1.11 (m, 2H), 1.52- 1.66 (m, 2 H), 1.69-1.82 (m, 2 H), 1.99 (s, 3 H), 3.00 (tt, J= 7.0, 3.5 Hz, 1 H), 4.01 (t, J = 6.4 Hz, 2 H), 4.42 (t, J = 7.3 Hz, 2H), 5.47 (s, 2 H), 7.31 (d, J = 5.5 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H),8.20 (d, J = 8.4 Hz, 1 H), 8.27 (d, J = 0.005538 >18058 5.5 Hz, 1 H),8.41 (s, 1 H)  65 N C—Cl

N ¹H NMR (360 MHz, DMSO- d₆) δ ppm 0.87-0.95 (m, 2 H), 1.01-1.12 (m, 2H), 1.05 (d, J = 7.0 Hz, 6 H), 1.53- 1.68 (m, 2 H), 1.69-1.84 (m, 2 H),2.43-2.56 (m, 1 H), 3.00 (tt, J = 6.9, 3.6 Hz, 1 H), 4.02 (t, J = 6.4Hz, 2 H), 4.43 (t, J = 7.3 Hz, 2 H), 5.47 (s, 2 H), 7.31 (d, J = 5.1 Hz,1 H), 7.37 (d, J = 8.4 Hz, 1 H), 8.20 0.005522 >18110 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 5.1 Hz, 1 H), 8.41 (s, 1 H)  66 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.82-0.96 (m, 2 H) 0.99-1.13 (m, 2 H)1.55- 1.67 (m, 2 H) 1.73 (m, J = 6.78 Hz, 2 H) 2.90-3.04 (m, 1 H) 3.59(t, J = 6.02 Hz, 2 H) 4.41 (t, J = 6.78 Hz, 2 H) 5.45 (s, 2 H) 7.21 (d,J = 4.77 Hz, 1 H) 7.33 (d, J = 8.28 Hz, 1 H) 7.78-7.94 (m, 4 H) 8.15-8.26 (m, 2 H) 8.38 (s, 1 H) 0.005904 >16939  67 N C—Cl

N ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.05 (m, 2 H) 1.13- 1.22 (m,5 H) 1.43-1.57 (m, 2 H) 1.77-1.91 (m, 2 H) 2.11 (br. s, 1 H) 2.89-2.98(m, 1 H) 3.81-3.90 (m, 1 H) 4.32-4.50 (m, 2 H) 5.40 (s, 2 H) 7.130.007909 >12643 (dd, J = 5.27, 0.75 Hz, 1 H) 7.23 (d, J = 8.53 Hz, 1 H)7.65 (d, J = 8.28 Hz, 1 H) 8.34 (d, J = 5.27 Hz, 1 H) 8.75 (s, 1 H)  68N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.83-1.00 (m, 2 H) 1.09 (m, J = 5.52Hz, 2 H) 1.36-1.53 (m, 2 H) 1.61- 1.81 (m, 2 H) 3.01 (m, J = 3.76 Hz, 3H) 3.51 (s, 3 H) 4.39 (t, J = 6.02 Hz, 2 H) 5.46 (s, 2 H) 7.05-7.19 (m,1 H) 7.30 (d, J = 4.77 Hz, 1 H) 7.36 (d, J = 8.28 Hz, 1 H) 8.18 (d, J =8.53 Hz, 1 H) 8.27 0.008191 >12208 (d, J = 5.02 Hz, 1 H) 8.40 (s, 1 H) 69 N C—F

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.94 (m, 2 H) 1.03-1.10 (m, 2 H)1.89- 2.01 (m, 2 H) 2.31-2.46 (m, 2 H) 2.98 (tt, J = 6.96, 3.58 Hz, 1 H)4.48 (t, J = 7.78 Hz, 2 H) 5.46 (s, 2 H) 7.08 (dd, J = 8.53, 1.00 Hz, 1H) 7.30 (dd, J = 0.075842 >1318 5.27, 0.75 Hz, 1 H) 8.27 (d, J = 5.27Hz, 1 H) 8.32 (dd, J = 8.53, 7.28 Hz, 1 H) 8.44 (d, J = 0.50 Hz, 1 H) 70 N C—H

N 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96-1.04 (m, 2 H) 1.13- 1.22 (m,2 H) 2.09-2.22 (m, 2 H) 2.91 (tt, J = 7.03, 3.64 Hz, 1 H) 4.02 (t, J =5.77 Hz, 2 H) 4.56 (t, J = 7.30 Hz, 1 H) 5.40 (s, 2 H) 7.13 (dd, J =5.27, 0.50 Hz, 1 H) 7.24 (dd, J = 8.03, 4.77 Hz, 1 H) 7.69 (dd,0.010969 >9116 J = 8.03, 1.51 Hz, 1 H) 8.35 (d, J = 5.27 Hz, 1 H) 8.56(dd, J = 4.77, 1.51 Hz, 1 H) 8.78 (d, J = 0.75 Hz, 1 H)  71 N C—Cl

N 1H NMR (400 MHz, DMSO- d₆) δ ppm 1.93-2.07 (m, 2 H) 2.30-2.47 (m, 2 H)4.44- 4.55 (m, 2 H) 4.85-4.97 (m, 2 H) 5.58 (s, 2 H) 7.39 (d, J = 8.53Hz, 1H) 7.46 (d, J = 5.27 Hz, 1 H) 8.23 (d, J = 8.28 Hz, 1 H) 8.34 (d, J= 0.000923 >108383 5.27 Hz, 1 H) 8.51 (s, 1 H)  72 N C—H

N 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.87-2.00 (m, 2 H) 2.21 (dt, J =10.35, 7.75 Hz, 2 H) 4.41-4.46 (m, 2 H) 4.49 (q, J = 8.53 Hz, 2 H) 5.48(s, 2H) 7.03 (d, J = 5.52 Hz, 1 H) 7.25-7.29 (m, 1 H) 7.67 (dd,0.003614 >2766 J = 8.03, 1.51 Hz, 1 H) 8.42 (d, J = 5.27 Hz, 1 H) 8.60(dd, J = 4.64, 1.38 Hz, 1 H) 8.90 (s, 1 H)  73 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.88-0.96 (m, 2 H) 1.03-1.12 (m, 2 H)1.46- 1.59 (m, 2 H) 1.70-1.84 (m, 2 H) 3.00 (tt, J = 6.96, 3.58 Hz, 1 H)3.11 (q, J = 6.61 Hz, 2 H) 4.43 (t, J = 7.53 Hz, 2 H) 5.47 (s, 2 H)7.03-7.12 (m, 2 H) 7.15-7.23 (m, 1 H) 7.27-7.32 (m, 1 H) 7.32- 7.40 (m,3 H) 7.77 (t, J = 5.65 Hz, 1 H) 8.20 (d, J = 8.53 Hz, 1 H) 8.27 (d, J =5.27 Hz, 1 H) 8.41 (s, 1 H) 0.015206 >6576  74 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.97 (m, 2 H) 1.00-1.14 (m, 2 H)1.40 (quin, J = 7.09 Hz, 2 H) 1.61- 1.77 (m, 2 H) 2.93-3.07 (m, 3 H)4.40 (t, J = 7.53 Hz, 2 H) 5.38 (s, 2 H) 5.46 (s, 2 H) 5.98 (t, J = 5.77Hz, 1 H) 7.30 (d, J = 5.27 Hz, 1 H) 7.35 (d, J = 8.53 Hz, 1 H) 8.20 (d,J = 8.53 Hz, 1 H) 8.27 (d, J = 5.02 Hz, 1 H) 8.40 (s, 1 H)0.005006 >1997  75 N C—Cl

N ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97-1.05 (m, 2 H), 1.11-1.22 (m,2 H), 1.17 (s, 6 H), 1.43-1.53 (m, 2 H), 1.74 (br. s., 1 H), 1.79-1.91(m, 2 H), 2.82-3.05 (m, 1 H), 4.40 (t, J = 7.5 Hz, 2 H), 5.390.001579 >63325 (s, 2 H), 7.11 (d, J = 5.0 Hz, 1 H), 7.20 (d, J = 8.3Hz, 1 H), 7.64 (d, J = 8.3 Hz, 1 H), 8.31 (d, J = 5.0 Hz, 1 H), 8.70 (s,1 H)  76 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.88-0.96 (m, 2 H) 1.04-1.11 (m, 2H)1.45 (m, J = 7.15, 7.15, 7.15, 7.15 Hz, 2 H) 1.64-1.77 (m, 2 H)2.96-3.08 (m, 3 H) 4.17 (dt, J = 30.62, 4.00 Hz, 2 H) 4.39 (t, J = 7.40Hz, 2 H) 4.56 (dt, J = 47.93, 3.80 Hz, 2 H) 5.46 (s, 2 H) 7.25-7.39 (m,3 H) 8.18 (d, J = 8.53 Hz, 1 H) 8.27 (d, J = 5.27 Hz, 1 H) 8.40 (s, 1 H)0.004078 >24518  77 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.96 (m, 2 H) 1.03-1.11 (m, 2 H)1.14 (d, J = 6.02 Hz, 6 H) 1.43 (m, J = 6.90, 6.90, 6.90, 6.90 Hz, 2 H)1.62-1.77 (m, 2 H) 2.90- 3.09 (m, 3 H) 4.39 (t, J = 7.28 Hz, 2 H) 4.72(dquin, J = 12.31, 5.96, 5.96, 5.96, 5.96 Hz, 1 H) 5.46 (s, 2 H) 7.02(t, J = 5.27 Hz, 1 H) 7.30 (d, J = 5.02 Hz, 1 H) 7.35 (d, J = 8.53 Hz, 1H) 8.18 (d, J = 8.53 Hz, 1 H) 8.27 (d, J = 5.27 Hz, 1 H) 8.40 (s, 1 H) 78 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.89-0.97 (m, 2 H), 1.04-1.13 (m, 2H), 1.29-1.41 (m, 2 H), 1.41-1.51 (m, 2 H), 1.53-1.66 (m, 4 H),1.68-1.87 (m, 4 H), 2.96-3.06 (m, 1 H), 3.68-3.84 (m, 1 H), 3.97 (t, J =6.3 Hz, 2 H), 4.45 (t, J = 7.3 Hz, 2 H), 0.005732 14406 5.47 (s, 2 H),7.08 (d, J = 7.0 Hz, 1 H), 7.30 (dd, J = 5.3, 0.5 Hz, 1 H), 7.36 (d, J =8.5 Hz, 1 H), 8.19 (d, J = 8.5 Hz, 1 H), 8.27 (d, J = 5.3 Hz, 1 H), 8.41(s, 1 H)  79 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.95 (m, 2 H), 1.02-1.10 (m, 2H), 1.60- 1.72 (m, 2 H), 1.75-1.88 (m, 2 H), 2.99-3.02 (m, 1 H), 3.69(s, 3 H), 4.09 (t, J = 6.5 Hz, 2 H), 4.45 (t, J = 7.4 Hz, 0.023345 17112 H), 5.47 (s, 2 H), 6.80-6.88 (m, 2 H), 7.28 (dd, J = 5.3, 0.8 Hz, 1H), 7.30-7.40 (m, 3 H), 8.20 (d, J = 8.5 Hz, 1 H), 8.26 (d, J = 5.0 Hz,1 H), 8.41 (s, 1 H), 9.37 (br. s., 1 H)  80 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.85-0.94 (m, 2 H) 1.00-1.10 (m, 2 H)1.64 (m, J = 7.28 Hz, 2 H) 1.82 (m, J = 7.72, 7.72, 7.72, 7.72 Hz, 2 H)2.06 (s, 3 H) 2.96 (tt, J = 6.96, 3.58 Hz, 1 H) 3.44 (q, J = 6.78 Hz, 2H) 4.45 (t, J = 7.40 Hz, 2 H) 5.47 (s, 2 H) 6.69 (t, J = 5.90 Hz, 1 H)7.24 (dd, J = 5.27, 0.50 Hz, 1 H) 7.35 (d, J = 8.53 Hz, 1 H)0.010386 >9628 7.57 (td, J = 7.50, 0.75 Hz, 1 H) 7.67 (td, J = 7.65,1.25 Hz, 1 H) 7.75 (dd, J = 7.40, 0.63 Hz, 1 H) 7.86 (d, J = 7.78 Hz, 1H) 8.19 (d, J = 8.53 Hz, 1 H) 8.24 (d, J = 5.27 Hz, 1 H) 8.42 (s, 1 H) 81 N C—H

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.98 (m, 2 H) 1.08 (m, J = 5.00Hz, 2 H) 1.14 (d, J = 5.27 Hz, 6 H) 1.37-1.54 (m, 2 H) 1.61-1.78 (m, 2H) 2.89-3.08 (m, 3 H) 4.37 (m, J = 5.50, 5.50 Hz, 2 H) 4.63-4.85 (m, 1H) 5.45 (s, 2 H) 6.96-7.12 (m, 1 H) 7.26 (dd, J = 7.40, 4.64 Hz, 1 H)7.30 (d, J = 4.77 Hz, 1 H) 8.07 (d, J = 7.53 Hz, 1 H) 8.26 (d, J = 4.77Hz, 1 H) 8.37 (d, J = 3.26 Hz, 1 H) 8.41 (s, 1 H) 0.072449 >1380  82 NC—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.97 (m, 2 H) 1.02-1.14 (m, 2 H)1.34- 1.87 (m, 12 H) 3.00 (m, J = 6.80, 3.80 Hz, 3 H) 4.39 (t, J = 7.15Hz, 2 H) 4.86-4.99 (m, 1 H) 5.46 (s, 2 H) 7.02 (t, J = 5.02 Hz, 1 H)7.30 (d, J = 5.27 Hz, 1 H) 7.35 (d, J = 0.017084 5649 8.53 Hz, 1 H) 8.18(d, J = 8.28 Hz, 1 H) 8.27 (d, J = 5.02 Hz, 1 H) 8.40 (s, 1 H)  83 NC—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.96 (m, 2 H), 1.02-1.11 (m, 2H), 1.58-1.71 (m, 2 H), 1.79-1.82 (m, 2 H), 2.99-3.05 (m, 1 H), 4.08 (t,J = 6.5 Hz, 2 H), 4.44 (t, J = 7.4 Hz, 2 H), 5.46 (s, 2 H), 7.30 (dd, J= 5.3, 0.5 Hz, 0.013992 4731 1 H), 7.35 (d, J = 8.5 Hz, 1 H), 7.49-7.55(m, 2 H), 7.61 (dd, J = 8.8, 2.5 Hz, 1 H), 8.17 (d, J = 8.3 Hz, 1 H),8.27 (d, J = 5.3 Hz, 1 H), 8.40 (s, 1 H), 9.07 (s, 1 H)  84 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.84-0.97 (m, 2 H), 1.06-1.15 (m, 2H), 1.68-1.72 (m, 2 H), 1.81-1.9 (m, 2 H), 2.92-3.07 (m, 1 H), 4.13 (t,J = 6.1 Hz, 2 H), 4.46 (t, J = 7.0 Hz, 2 H), 5.47 (s, 2 H), 7.21-7.43(m, 4 H), 7.68 0.018911 354 (d, J = 5.3 Hz, 1 H), 8.20 (d, J = 8.5 Hz, 1H), 8.26 (d, J = 5.3 Hz, 1 H), 8.41 (s, 1 H), 9.82 (br. s., 1 H)  85 NC—H

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 1.63-1.90 (m, 4 H) 4.36-4.57 (m, 4 H)4.92 (q, J = 9.20 Hz, 2 H) 5.56 (s, 2 H) 7.27 (dd, J = 8.16, 4.64 Hz, 1H) 7.46 (d, J = 5.02 Hz, 1 H) 8.09 (dd, J = 8.03, 1.25 Hz, 1 H) 8.33 (d,J = 0.008536 1436 5.27 Hz, 1 H) 8.37 (dd, J = 4.64, 1.13 Hz, 1 H) 8.51(s, 1 H)  86 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.87-0.96 (m, 2 H), 1.02-1.11 (m, 2H), 1.61- 1.73 (m, 2 H), 1.83 (m, 2 H), 2.99 (m, 1 H), 4.12 (t, J = 6.5Hz, 2 H), 4.46 (t, J = 7.3 Hz, 2 H), 5.47 (s, 2 H), 7.28 (dd, J = 5.3,0.8 Hz, 1 H), 0.03677  263 7.29-7.33 (m, 2 H), 7.35 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2 H), 8.20 (d, J = 8.5 Hz, 1 H), 8.26 (d, J =5.0 Hz, 1 H), 8.41 (s, 1 H), 9.72 (br. s., 1 H)  87 N C—Cl

C—F ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.85-1.97 (m, 2 H) 2.14- 2.29(m, 2 H) 4.38-4.54 (m, 4 H) 5.40 (s, 2 H) 6.87 (td, J = 9.03, 2.51 Hz, 1H) 6.98 (dd, J = 8.53, 4.02 Hz, 1 H) 7.30 (d, J = 8.53 Hz, 1 H) 7.470.002038 >49069 (dd, J = 8.16, 2.38 Hz, 1 H) 7.64 (d, J = 8.53 Hz, 1 H) 88 N C—Cl

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.82-1.01 (m, 8 H) 1.08 (m, J = 5.77Hz, 2 H) 1.49-1.67 (m, 2 H) 2.96- 3.06 (m, 0 H) 3.23 (d, J = 2.26 Hz, 2H) 4.30-4.46 (m, 2 H) 4.69-4.83 (m, 0 H) 5.46 (s, 2 H) 7.34 (d, J = 5.52Hz, 1 H) 7.36 (d, J = 8.28 Hz, 1 H) 0.011068 >4517 8.07 (d, J = 8.28 Hz,1 H) 8.29 (d, J = 5.02 Hz, 1 H) 8.43 (s, 1 H)  89 N C—H

C—F ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.82-1.99 (m, 2 H) 2.12- 2.30(m, 2 H) 4.39-4.55 (m, 4 H) 5.43 (s, 2 H) 6.80-6.90 (m, 1 H) 6.94-7.05(m, 1 H) 7.19-7.33 (m, 1 H) 7.50 (dd, J = 8.16, 2.38 Hz, 1 H)0.049076 >2037 7.68 (dd, J = 8.28, 1.51 Hz, 1 H) 8.61 (dd, J = 4.77,1.51 Hz, 1 H)  90 N C—Cl

N ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (d, J = 6.52 Hz, 6 H),1.52-1.64 (m, 2 H), 1.72 (tt, J = 13.21, 6.62 Hz, 1 H), 4.26- 4.40 (m, 2H), 4.50 (q, J = 8.53 Hz, 2 H), 5.43 (s, 2 H), 7.02 (d, J = 5.27 Hz, 1H), 7.23 (d, J = 8.28 Hz, 1 H), 7.62 (d, 0.0026  36156 J = 8.28 Hz, 1H), 8.39 (d, J = 5.27 Hz, 1 H), 8.78 (s, 1 H)  91 N C—H

N ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88-1.05 (m, 2 H) 1.11- 1.22 (m,2 H) 1.90-2.11 (m, 2 H) 2.68 (t, J = 7.78 Hz, 2 H) 2.80-3.01 (m, 1 H)4.40 (t, J = 7.80 Hz, 2 H) 5.38 (s, 2 H) 7.08-7.14 (m, 3 H) 7.15- 7.25(m, 2 H) 7.27-7.32 (m, 0.01216  >8223 2 H) 7.50 (dd, J = 8.03, 1.51 Hz,1 H) 8.35 (d, J = 5.27 Hz, 1 H) 8.55 (dd, J = 4.77, 1.51 Hz, 1 H) 8.75(s, 1 H)  92 N C—Cl

C—F ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 (d, J = 6.52 Hz, 6 H),1.55 (m, J = 15.80, 7.50 Hz, 2 H), 1.62-1.78 (m, 1 H), 4.36 (m, J =16.31 Hz, 2 H), 4.46 (q, J = 8.53 Hz, 2 H), 5.38 (s, 2 H), 6.84 (td, J =9.03, 2.26 Hz, 1 H), 6.96 (dd, J = 8.53, 4.27 Hz, 0.00672  13572 1 H),7.25 (d, J = 8.50 Hz, 1 H), 7.43 (dd, J = 8.28, 2.26 Hz, 1 H), 7.61 (d,J = 8.28 Hz, 1 H)  93 N C—H

C—F ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.80-0.92 (m, 2 H) 0.97-1.13 (m, 2H) 1.89- 2.05 (m, 2 H) 2.56-2.70 (m, 2 H) 2.83-2.99 (m, 1 H) 4.42 (t, J= 7.53 Hz, 2 H) 5.39 (s, 2 H) 6.87-6.98 (m, 1 H) 7.13-7.30 (m, 8 H) 8.02(dd, J = 8.16, 1.38 Hz, 0.031484 >3176 1 H) 8.37 (dd, J = 4.77, 1.51 Hz,1 H)  94 N C—H

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.75-0.96 (m, 2 H) 0.99-1.13 (m, 2 H)2.03- 2.20 (m, 2 H) 2.73-2.86 (m, 2 H) 2.91-3.06 (m, 1 H) 4.48 (t, J =7.30 Hz, 2 H) 5.47 (s, 2 H) 7.12-7.34 (m, 4 H) 7.67 (dd, J = 8.03, 2.01Hz, 1 H) 8.05 (d, J = 7.78 Hz, 0.1258  >748 1 H) 8.26 (d, J = 5.27 Hz, 1H) 8.36 (d, J = 3.51 Hz, 1 H) 8.42 (s, 1 H) 8.46 (d, J = 4.02 Hz, 1 H) 95 N C—H

C—F ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.78-0.92 (m, 2 H) 0.97-1.09 (m, 2H) 1.90 (s, 2 H) 2.06 (br. s, 3 H) 2.28- 2.42 (m, 2 H) 2.83-3.00 (m, 1H) 4.39 (t, J = 7.40 Hz, 2 H) 5.37 (s, 2 H) 6.84-7.01 (m, 1 H) 7.14-7.30(m, 4 H) 7.99 (dd, J = 8.03, 1.25 Hz, 1 H) 8.37 (dd, J = 4.64, 1.38 Hz,1 H)  96 N C—H

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.77-0.96 (m, 2 H) 1.00-1.12 (m, 2 H)1.86- 1.98 (m, 2 H) 2.06 (br. s, 3 H) 2.37 (t, J = 7.78 Hz, 2 H) 2.97(tt, J = 6.93, 3.48 Hz, 1 H) 4.40 (t, J = 7.15 Hz, 2 H) 5.43 (s, 2 H)7.25 (dd, J = 8.16, 4.64 Hz, 2 H) 7.29 (d, J = 5.27 Hz, 1 H) 7.99 (d, J= 8.03 Hz, 1 H) 8.26 (d, J = 5.27 Hz, 1 H) 8.37 (dd, J = 4.77, 1.51 Hz,1 H) 8.42 (s, 1 H)  97 N CMe₂ NH₂

N  98 N C—H

N ¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.77-0.94 (m, 2 H) 0.98-1.13 (m, 2 H)2.01 (quin, J = 7.72 Hz, 2 H) 2.58- 2.73 (m, 2 H) 2.88-3.05 (m, 1 H)4.42 (t, J = 7.53 Hz, 2 H) 5.46 (s, 2 H) 7.14-7.37 (m, 6 H) 8.04 (d, J =7.53 Hz, 1 H) 8.27 (d, J = 5.27 Hz, 1 H) 8.36 (d, J = 4.27 Hz, 1 H) 8.44(s, 1 H)

TABLE 5 WT activity EC₅₀ SI structure ¹H NMR (μM) CC₅₀/EC₅₀ 62

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04- 1.11 (m, 2 H) 1.15-1.22 (m, 2H) 1.65-1.73 (m, 2 H) 1.80 (br. s, 1 H) 1.98-2.15 (m, 2 H) 2.87-3.00 (m,1 H) 3.70-3.80 (m, 5 H) 4.36 (t, J = 7.40 Hz, 2 H) 5.89 (s, 2 H) 7.18(d, J = 8.28 Hz, 1 H) 7.35 (d, J = 5.02 Hz, 1 H) 7.63 (d, J = 8.53 Hz, 1H) 8.40 (d, J = 5.27 Hz, 1 H) 0.294144   >339 49

1.450474   >68 105

0.000316 >330179

The invention claimed is:
 1. A method of treating a respiratorysyncytial viral (RSV) infection comprising administering to a subject inneed thereof an anti-virally effective amount of a compound of formulaI, or a N-oxide, addition salt, quaternary amine, or a stereochemicallyisomeric form thereof,

wherein each X is independently C or N, wherein at least one X is N;each Y is independently C or N; each R₁ is selected from the groupconsisting of H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkoxy,N(R₅)₂, CO(R₆), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,CF₃, OCF₃, B(OH)₂, and B(O—C₁-C₆alkyl)₂, wherein if X is C, R₁ ispresent, and if X is N, R₁ is absent; R₂ is —(CR₇R₈)_(n)-R₉; R₃ isselected from the group consisting of H, C₁-C₁₀alkyl, C₃-C₇cycloalkyl,C₂-C₁₀alkenyl, SO₂-R₇, CH₂CF₃ and a 4 to 6 membered saturated ringcontaining an oxygen atom; each R₄ is independently selected from thegroup consisting of H, C₁-C₆alkyl, C₁-C₆cycloalkyl, C₁-C₆alkoxy, CO(R₇),COO(R₇), CF₃ and halogen, wherein if Y is C, R₄ is present, and if Y isN, R₄ is absent; each R₅ is independently selected from the groupconsisting of H, C₁-C₆alkyl, COOCH₃, and CONHSO₂CH₃; each R₆ isindependently selected from the group consisting of OH, O(C₁-C₆alkyl),NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),NHSO₂(C₃-C₇cycloalkyl), and N(C₁-C₆-alkyl)₂; R₇ and R₈ are eachindependently selected from the group consisting of H, C₁-C₁₀alkyl, andC₃-C₇cycloalkyl, or R₇ and R₈ taken together form a 4 to 6 memberedaliphatic ring, said ring optionally contains a heteroatom selected fromthe group consisting of N, S, and O; R₉ is selected from the groupconsisting of H, R₁₀, C₁-C₆alkyl, OH, CN, F, CF₂H, CF₃, CONR₇R₈, COOR₇,CON(R₇)SO₂R₈, CON(R₇)SO₂N(R₇R₈), NR₇R₈, NR₇COOR₈, OCOR₇, O-Benzyl,NR₇SO₂R₈, SO₂NR₇R₈, SO₂R₂ , OCONR₇R₈, OCONR₇R₁₀, N(R₇)CON(R₇R₈),N(R₇)COOR₁₀, phtalimido, 2-methyl-benzothiophene(1,1)dioxide, and a 4 to6 membered saturated ring containing an oxygen atom; n is an integerfrom 2 to 6; and R₁₀ is selected from the group consisting of C₁-C₆alkyl, C₃-C₇cycloalkyl, phenyl, pyridine and pyrazole, wherein R₁₀ isoptionally substituted with one or more substituents comprising CF₃,CH₃, OCH₃, OCF₃ or halogen.
 2. A method according to claim 1 wherein R₃is selected from the group consisting of H, C₁- C₁₀alkyl,C₃-C₇cycloalkyl, C₂-C₁₀alkenyl, SO₂-R₂, and a 4 to 6 membered saturatedring containing an oxygen atom; and R₉ is selected from the groupconsisting of H, C₁-C₆alkyl, OH, CN, F, CF₂H, CF₃, CONR₇R₈, COOR₇,CON(R₂)SO₂R₈, CON(R₇)SO₂N(R₇R₈), NR₇R₈, NR₇COOR₈, OCOR₇, O-Benzyl,NR₇SO₂R₈, SO₂NR₇R₈, SO₂R₇ , and a 4 to 6 membered saturated ringcontaining an oxygen atom.
 3. A method according to claim 1 wherein oneX is N, said N being in either of the two positions ortho to theimidazole ring.
 4. A method according to claim 1, wherein R₁ is H orhalogen.
 5. A method according to claim 1, wherein R₁ in the paraposition to C—N—R₂ is selected from the group consisting of H, halogen,and CH₂—NH₂, and all other R₁ are H.
 6. A method according to claim 1,wherein R₇ and R₈ are H, and n is 2-4.
 7. A method according to claim 1,wherein R₉ is selected from the group consisting of OH, F, CF₂H, CF₃,C₁-C₆alkyl, and SO₂R₇.
 8. A method according to claim 1, wherein R₃ isselected from the group consisting of C₃-C₇cycloalkyl, and a 4 memberedsaturated hydrocarbon containing an oxygen atom.
 9. A method accordingto claim 1, wherein R₃ is cyclopropyl or CH₂CF₃.
 10. A method accordingto claim 1, wherein the Y that is in para position to N—R₃ is N, andeach other Y is C.
 11. A method according to claim 10, wherein the R₄ onthe Y that is in para position to N—R₃ is F.
 12. A method according toclaim 1, wherein each R₄ is H.